Antiallergic cyclic sulphur compounds

ABSTRACT

Certain tricyclic thioxanthone-10,10-dioxide compounds each of which is substituted in the 1-,2-,3- or 4-position by a carboxyl or (5-tetrazolyl) group and each of which is optionally substituted in the 5-,6-,7- or 8-position by a second carboxyl or (5-tetrazolyl) group or a substituent selected from cyano, halogen, nitro, alkyl, alkoxy, acyl, amino, acylamino, thioalkyl, alkylsulphinyl and alkylsulphonyl, as well as salts, and optionally substituted esters and amides of the carboxyl substituted compounds and alkyl derivatives of the tetrazolyl substituted compounds, are useful for the relief or prophylaxis of allergic conditions.

This application is a continuation-in-part of U.S. Pat. Application Ser.No. 361,523 filed May 18, 1973, now U.S. Pat. No. 3,905,989, issuedSept. 16, 1975.

The invention relates to tricyclic compounds having medicinalproperties, the synthesis of the compounds and their adaptation formedicinal use.

It has been found that tricyclic compounds of formula I, as definedhereinbelow, are active in mammals and in in vitro mammalianpreparations as inhibitors of allergic reactions associated withreaginic antibodies of the kind responsible for asthma in man, and thatthis effect is attributable to the suppression of the release ofanaphylactic mediators.

In formula I, Z¹ is a substituent in the 1-,2-,3-, or 4-position and iscarboxyl, 5-tetrazolyl, 5-(1-alkyl) tetrazolyl, or 5-(2-alkyl)tetrazolylin which the alkyl groups have 1 to 6 carbon atoms and are eachoptionally substituted by a hydroxyl group or a basic or acidic group;Z² is hydrogen or a substituent in the 5-,6-, 7-, or 8-position selectedfrom the values of the group Z¹ as defined above or is alkylsulphonyl,alkylsulphinyl, thioalkyl, amino, acylamino, nitro, cyano, halogenpreferably chlorine or bromine, acyl, alkyl or alkoxy wherein the"alkyl" moiety of each of the acyl, alkyl, alkoxy, thioalkyl, acylamino,alkylsulphinyl and alkylsulphonyl groups has 1 to 6 carbon atoms; and Z³is carbonyl; together with salts of said compounds and when at least oneof Z¹ and Z² is a carboxyl group, esters and amides of said compounds.

The inhibition activity of the compounds of formula I has beendemonstrated (a) in tests using the response of passive cutaneousanaphylaxis (PCA test) in which is measured the skin reaction producedas the result of interaction between specific antigen injectedintravenously and cell-fixed reaginic antibody previously injected intothe skin of a mammal (see for example Z. Ovary: Fedn. Proc. Am. Soc.exp. Biol. 24, 94 (1965)), (b) by measurement of the amount of histaminereleased after antigen challenge of peritoneal mast cells from activelysensitised rats (see for example, 1. Acta Pharmacol. et Toxicol. 30,supp. 1 (1971), 2. Thorax, 27/1, 38 (1972)), and (c) by measurement ofthe histamine released from human chopped lung tissue passivelysensitised in vitro with reaginic antibody when challenged with thehomogolous antigen (Br. Med. J. 3,272 (1968)). The activity of acids offormula I has been demonstrated as described hereinabove using solutionsof the anion.

For the sake of convenience, compounds of formula I wherein either of Z¹and Z² is or both are an alkyl carboxylate group, are hereinafterreferred to as `esters` of formula I. Similarly references to `amides`of formula I shall be construed as references to compounds of formula Iwherein one or both of Z¹ and Z² is an optionally substitutedcarboxamide, and references to `salts` of formula I shall mean salts offormula I wherein one or both of Z¹ and Z² is a salt of the acid.

Pharmaceutically acceptable salts of compounds of formula I includeammonium salts, alkali metal salts such as sodium and potassium salts,alkaline earth salts such as magnesium and calcium salts, and salts oforganic bases, for example, amine salts derived from mono-, di-, ortri-lower alkyl or lower alkanolamines such as triethanolamine anddiethylaminoethylamine and salts with heterocyclic amines such aspiperidine pyridine, piperazine and morpholine. Especially valuable forintravenous and pulmonary administration are water soluble salts, mostpreferably those having a solubility in water of at least 1 mg/ml.

For the purposes of medicinal administration, the carboxylate salt groupmay be a salt of any pharmaceutically acceptable cation, since thepharmacological activity of the salts is associated with the anion.

Suitable amides include amides derived from primary or secondary,aliphatic amines such as N-alkyl and N,N-dialkyl amines from examplediethylamine. Suitable esters include esters derived from alkylalcohols. The alkyl moieties of the alkyl esters and N-alkyl andN,N-dialkyl carboxamides, preferably each have 1 to 6 carbon atoms, mostdesirably 1 to 4 carbon atoms.

Each of the alkyl moieties of the esters, alkyltetrazoles and amides isoptionally substituted by at least one hydroxy, basic or acidicsubstituent. Suitable basic substituents include amino groups optionallysubstituted by one or two alkyl groups and heterocyclic amino groupssuch as piperidine or morpholine. The esters and amides having basicsubstituents as well as the amides themselves may be in the form ofpharmaceutically acceptable acid addition salts.

Suitable acidic substituents include 5-tetrazolyl groups and carbonxylgroups, and their pharmaceutically acceptable salts.

Included within the scope of compounds of formula (I) are tricycliccompounds of formula (III) wherein Z¹ is a substituent in the 1-,2-,3-or 4-position and is a carboxyl group, a carboxylate salt group, analkyl carboxylate group wherein the alkyl moiety has 1 to 6, preferably1 to 4 carbon atoms, a carboxamide group optionally N-substituted byalkyl having 1 to 6, preferably 1 to 4 carbon atoms, a 5-tetrazolylgroup a 5-tetrazolyl salt group, a 5-(1-alkyl)tetrazolyl group or a5-(2-alkyl) tetrazolyl group in which the alkyl groups have 1 to 6carbon atoms and are each optionally substituted by a basic group;

Z² is hydrogen or a substituent in the 5-,6-,7-, or 8-position and hasthe same values as the group Z¹ as defined above or is an alkylsulphonylgroup, an alkylsulphinyl group, a thioalkyl group, an amino group, anacylamino group, a nitro group, a cyano group, a halogen atom, an acylgroup, an alkyl group or an alkoxy group wherein the "alkyl" moiety ofeach of the acyl, alkyl, alkoxy, thioalkyl, acylamino, alkylsulphinyland alkylsulphonyl groups has 1 to 6 carbon atoms, and Z³ is carbonyl.

Especially preferred sulphone compounds of formula (I) include tricycliccompound of formula (IV) wherein Z³ is as defined in formula (I), and Z¹is selected from a carboxyl group, a carboxylate salt group, an alkylcarboxylate group having 1 to 4 carbon atoms in the alkyl moiety, acarboxamide group opitionally N-substituted by an alkyl group having 1to 4 carbon atoms, a 5-tetrazolyl group and a 5-tetrazolyl salt group.

Other preferred compounds of formula (I) include tricyclic compounds offormula (V) wherein Z³ is as defined in formula (I), and Z¹ and Z² arethe same or different and each is selected from a carboxyl group, acarboxylate salt group, an alkyl carboxylate group having 1 to 6 carbonatoms, a carboxamide group optionally N-substituted by an alkyl grouphaving 1 to 6 carbon atoms, a 5-tetrazolyl group, and a 5-tetrazolylsalt group.

Compounds of formula (I) which show a very high anti-allergic activityon oral administration include 3-carboxythioxanthone-10,10-dioxide and3-(5-tetrazolyl)thioxanthone-10,10-dioxide, and salts of thesecompounds, especially alkali metal salts including sodium and potassiumsalts.

Preferred compounds of the present invention also include tricycliccompounds of formula (II) wherein Z¹ is a substituent in the 3-positionand is carboxyl or tetrazolyl and Z² is hydrogen or a substituent in the5-,6-,7- or 8-position selected from the values of the group Z¹ asdefined above or is nitro, chlorine, bromine, or alkyl having 1 to 6carbon atoms; and the pharmaceutically acceptable salts of saidcompounds.

Novel thioxanthone-10,10-dioxide compounds of the present inventioninclude tricyclic compounds of formula IX wherein Z¹ is a substituent inthe 1-,2-,3-, or 4-position and is carboxyl, a carboxylate salt group,an alkyl carboxylate group wherein the alkyl moiety has 1 to 6,preferably 1 to 4 carbon atoms, a 5-tetrazolyl salt group,5-(1-alkyl)tetrazolyl or 5-(2-alkyl) tetrazolyl in which the alkylgroups have 1 to 6 carbon atoms and are each optionally substituted by ahydroxyl group or a basic or acidic group; and Z² is a hydrogen or asubstituent in the 5-,6-,7-, or 8-position and is alkylsulphonyl,alkylsulphinyl, thioalkyl, amino, acylamino, nitro, cyano, halogenpreferably chlorine or bromine, acyl, alkyl, alkoxy wherein the "alkyl"moiety of each of the acyl, alkyl, alkoxy, thioalkyl, acylamino,alkylsulphinyl and alkylsulphonyl groups has 1 to 6 carbon atoms;together with salts of said compounds and when at least one of Z¹ and Z²is a carboxyl group, their esters and amides other than2-carboxythioxanthone-10,10-dioxide and its methyl ester;3-carboxy-thioxanthone-10,10-dioxide;7-nitro-2-carboxythioxanthone-10,10-dioxide and its amide;2,6-dicarboxythioxanthone-10,10-dioxide and its dimethyl ester: and8-chloro-2-carboxythioxanthone-10,10-dioxide.

Novel tetrazolyl compounds and their derivatives of the presentinvention include tricyclic compounds of formula (XI) wherein Z¹ is asubstituent in the 1-,2-,3-, or 4-position and is 5-tetrazolyl, a5-tetrazolyl salt group, 5-(1-alkyl)tetrazolyl or 5-(2-alkyl)tetrazolylin which the alkyl groups have 1 to 6 carbon atoms and are eachoptionally substituted by a hydroxyl group or a basic or acidic group;Z² is a hydrogen or a substituent in the 5-,6-,7- or 8-position selectedfrom the values of the group Z¹ as defined above or is alkylsulphonyl,alkylsulphinyl, thioalkyl, amino, acylamino, nitro, cyano, halogenpreferably chlorine or bromine, acyl, alkyl, or alkoxy wherein the"alkyl" moiety of each of the acyl, alkyl, alkoxy, thioalkyl, acylamino,alkylsulphinyl and alkylsulphonyl groups has 1 to 6 carbon atoms,carboxyl, a carboxylate salt group, an alkyl carboxylate group whereinthe alkyl moiety has 1 to 6, preferably 1 to 4 carbon atoms, or acarboxamide group optionally N-substituted by alkyl having 1 to 6,preferably 1 to 4 carbon atoms; and Z³ is carbonyl.

Novel compounds of the present invention also include the solidtricyclic compounds of formula (XII) wherein Z¹ is a substituent in the1-,2-,3- or 4-position and is a pharmaceutically acceptable carboxylatesalt group, 5-tetrazolyl, a 5-tetrazolyl salt group,5-(1-alkyl)tetrazolyl or 5-(2-alkyl)tetrazolyl in which the alkyl groupshave 1 to 6 carbon atoms and are each optionally substituted by ahydroxyl group or a basic or acidic group; Z² is a hydrogen or asubstituent in the 5-, 6-, 7-, or 8-position selected from the values ofthe group Z¹ defined above or is alkylsulphonyl, alkylsulphinyl,thioalkyl, amino, acylamino, nitro, cyano, halogen preferably chlorineor bromine, acyl, alkyl, or alkoxy wherein the "alkyl" moiety of theacyl, alkoxy, thioalkyl, acylamino, alkylsulphinyl and alkylsulphonylgroups has 1 to 6 carbon atoms or a carboxyl; and Z³ is carbonyl; andwhen Z² includes a carboxyl group, esters or amides thereof;

The compounds of formula I may be prepared by known chemical techniques.In general, the methods include cyclisation wherein the central ring iscompleted by ring closure, hydrolysis, oxidation or reduction ofprecursors leading to both of the groups Z¹ and Z² by a variety oftechniques. Examples of the preparation of certain compounds of formulaI by these methods are described at the end of this specification. Thesegeneral synthetic procedures are also applicable in some instances tothe preparation of intermediates.

The cyclisation preparative methods in general include the formation asthe final step of one or both of the bridges of the central ring. Forexample compounds of formula XIII wherein Z¹, Z² and Z³ are defined informula I, may be reacted with chlorosulphonic acid to providecorresponding compounds of formula I, or using chlorosulphonyl compoundsof formula XIV wherein Z¹, and Z² and Z³ are defined in formula I, thecorresponding compounds of formula I may be prepared, by ring closureusing a Lewis acid, for example aluminium chloride with heat.

Reaction of a Lewis acid or a protonic acid with substituted diphenylsulphones of formula XV wherein Z¹ and Z² are defined in formula I andR¹ is a carboxy group or a derivative thereof such as a nitrile, amide,aldehyde, or acid chloride, produces the thioxanthone 10,10-dioxides.

Preferred protonic acids are polyphosphoric acid (tetraphosphoric acid)and sulphuric acid. Suitable Lewis acids include aluminium trichlorideand boron trifluoride. The reaction is preferably carried out at atemperature from 50° to 300° C.

A variety of oxidation techniques may be used to prepare the compoundsof formula I by completion of one or both of the bridges of the centralring. For example, the thioxanthone-10,10-dioxides (in formula I, Z³ iscarbonyl) may be prepared by oxidation of the correspondingthioxanthene-10,10-dioxides (in formula I, Z³ is methylene), using forexample Triton B, pyridine and oxygen. Compounds of formula I may alsobe prepared by oxidation of the corresponding sulphoxides and sulphidesto form the sulphones, using for example hydrogen peroxide and aceticacid.

The compounds of formula I may also be prepared by formation of one orboth of the groups Z¹ and Z² as the final step.

Thus in formula I wherein one or both of Z¹ and Z² are tetrazolyl or(1-alkyl)tetrazolyl groups, these compounds may be prepared by reactionof hydrazoic acid or a salt thereof or nitrous acid with an appropriatecompound of formula XVIII wherein Y⁷ is a group Z¹ as defined in formulaI or a tetrazolyl group precursor and Y⁸ is a group Z² as defined informula I or a tetrazolyl group precursor, provided that at least one ofY⁷ and Y⁸ is a tetrazolyl group precursor.

When hydrazoic acid or a salt thereof is used, a suitable tetrazolylgroup precursor is a group ##STR1## wherein R³ and R⁴ together form abond (nitrile), R³ is hydrogen or alkyl and R⁴ is alkoxy having 1 to 6carbon atoms (imidoester), thioalkyl having 1 to 6 carbon atoms(imidothioester), --NH--NH₂ (amidrazone), or amino (amidine) or R³ ishydroxy and R⁴ is amino (amidoxime), or R³ is alkyl and R⁴ is halogen(imidohalide). In the case of amidoximes and nitriles, only tetrazolylcompounds may be produced and in the case of imidohalides onlyalkyltetrazolyl compounds may be produced. The reaction is preferablycarried out in a polar aprotic liquid medium using a salt of hydrazoicacid.

When nitrous acid is used a suitable tetrazolyl precursor group is agroup ##STR2## wherein R³ is hydrogen or alkyl and R⁴ is --NH--NH₂(amidrazone) or R³ is hydrogen and R⁴ is amino (amidine). In the lattercase, reduction of the intermediate nitrosation product, with or withoutprior isolation, using for example sodium amalgam, is required to givethe corresponding tetrazolyl compound.

The tetrazolyl compounds of formula I thus prepared may be isolated asthe free acid or as a tetrazolyl salt, and the one converted to theother in known manner and as specifically described below in relation tothe carboxylic acids of formula I and their salts.

The 5-(1- and 2-alkyl)tetrazolyl compounds of formula I may be made fromthe corresponding tetrazolyl compounds of formula I or their salts byalkylation.

The carboxylic acids of formula I, wherein one or both of Z¹ and Z² arecarbonyl may be prepared by a variety of methods which include as thefinal step the formation of the carboxyl group. These compounds may beisolated as the free acid, as salts thereof, or converted to amides oresters of formula I, depending upon the nature of the desired products.Thus they may be prepared by hydrolysis of a compound of formula XIXwherein at least one of Y¹ and Y² is a carboxyl group precursor, such asa nitrile group, trichloromethyl group or a group COL¹ wherein L¹ is aleaving group, such as a nucleophilic atom or a group, for example, atrichloromethyl group, an optionally substituted amino group, a halogenatom or an alkoxy group, when the other is Z¹ or Z² as defined informula I, as appropriate, or is Y¹ as defined above; and Z³ has themeaning defined in formula I. Hydrolysis is conveniently effected byheating a compound of formula XIX with a base or a dilute aqueousmineral acid optionally with an organic acid. For example, one may usedilute sulphuric acid or dilute hydrochloric acid with acetic acid.

By means of nucleophilic substitution reactions analogous to hydrolysis,for example, alcoholysis and ammonolysis, esters and amides of formula Imay be prepared directly from compounds of formula XIX. Thus reaction ofa compound of formula XIX with an appropriate alcohol yields an ester offormula I, and reaction with ammonia or an appropriate primary orsecondary amine yields an amide of formula I.

The carboxylic acids of formula I and their salts may also be made byoxidation of a compond of formula XX wherein Y⁵ is an alkyl group, anacyl group or a group Z¹ as defined in formula I, Z³ is as defined informula I, and Y⁶ is an alkyl group, an acyl group or a group Z² asdefined in formula I provided that at least one of Y⁵ and Y⁶ is an alkylor acyl group. Oxidation of compounds wherein Y⁵ and/or Y⁶ are loweralkyl groups may be effected with such conventional oxidising agents asacid or alkaline aqueous potassium permanganate solution; chromiumtrioxide, for example, with acetic acid or sulphuric acid; oxygen in thepresence of a conventional catalyst such as vanadium, cobalt andmanganese salts or oxides; or aqueous solutions of dichromate salts.

Oxidation of compounds wherein Y⁵ and/or Y⁶ are acyl groups may beeffected with such conventional oxidising agents as chromium trioxide,for example, with acetic acid or sulphuric acid; aqueous solutions ofsalts of hypochlorous and hypobromous acids in the presence of a base;sodium or potassium dichromate with acetic acid; or nitric acid. Theseoxidation procedures are advantageously effected with heating in theliquid phase.

The compounds of formula I wherein Z² is other than hydrogen, alkyl,acyl, carboxyl or a derivative thereof or tetrazolyl or a derivativethereof may also be made by formation of the group Z² as the final step.Such compounds are prepared by introducing an alkylsulphonyl group,alkylsulphinyl group, alkylthio group, amino group, acylamino group,nitro group, cyano group, halogen atom or alkoxy group into anappropriate compound of formula XXII wherein Z¹ and Z³ are as defined informula I and Q is hydrogen, a leaving group or a precursor, by knownmethods.

Thus where Z² is amino, the compounds may be made by reduction of thecorresponding nitro compounds which themselves may be made by nitration.The amino compounds may be converted into acylamino compounds byacylation and into the corresponding diazonium compounds of formulaXXIII wherein Z¹ and Z³ are defined in formula I and W is an anion, forexample chloride, bromide or hydrogen sulphate by reaction with nitrousacid. These diazonium compounds may be converted by known methods to thealkoxy compounds (by reaction with water and alkylation of the resultinghydroxy compounds); to the halo compounds (by the Sandmeyer reactionusing cuprous bromide or chloride; by the Gattermann reaction using acopper catalyst to produce bromo or chloro compound where W is thechloride or bromide ion; by the Balz-Schiemann reaction using thefluoroborate diazonium salt to produce the fluoro compounds; or by usingan alkali metal iodide to produce the iodo compounds); to the nitrilecompounds (by modified Sandmeyer or Gattermann reactions using cuprouscyanide or potassium cyanide and copper powder); to thiols and alkylthiocompounds (by the Leuckart synthesis by formation of diazoxanthates ordiazothioxanthates from the diazo compounds and alkali metal alkylxanthates or thioxanthates respectively which are decomposed in faintlyacid cuprous media to the alkylthio compounds and to thiols onhydrolysis). The thiols may if desired be alkylated to the alkylthiocompounds of formula I, and these in turn oxidised to alkylsulphinyl oralkylsulphonyl compounds of formula I.

In the operation of the foregoing synthetic methods, it will also beunderstood that where the groups Z¹ and Z² are formed prior to thecomplete formation of the desired compound, then in some instances Z¹and/or Z² must be protected from inter-reaction in the final syntheticstage or stages; thus for example when Z² is an amino group, it may beprotected by acylation and the acylamino group subsequently hydrolysed.In other instances it is advisable to form the groups Z¹ and/or Z² asthe final synthetic step, if the group(s) would react in the finalsynthetic stage(s).

Pharmaceutically acceptable salts of tetrazoles or carboxylic acids offormula (I) are prepared by any conventional method, for example byneutralising the corresponding carboxylic acid or tetrazole with anappropriate Bronsted base, or by double decomposition of a salt of anacid or tetrazole of formula (I) so as to produce the desired salt of anappropriate pharmaceutically acceptable cation. The carboxylic acid ortetrazole may be either the isolated acid or tetrazole, or may bepresent in solution in the reaction mixture resulting from a preparationof the compound, for example by such a method as described hereinbefore.Suitable Bronsted bases include organic bases such as ethanolamine, andbases containing ammonium, and alkali metal and alkaline earth metalcations. Double decomposition may be effected advantageously in an anionexchange resin wherein a solution of a salt of an acid or tetrazole offormula (I) is passed through a cation exchange resin, the resin beingcharged with a pharmaceutically acceptable cation of the suitable base.Double decomposition may also be effected in ordinary solution between asalt of an acid or tetrazole of formula I and a salt of the desiredpharmaceutically acceptable cation.

Specifically, pharmaceutically acceptable salts of carboxylic acids offormula I may be prepared by reaction in a polar medium of a compound offormula XXIV wherein R⁷ and R⁸ are the same or different and each isselected from a carboxylic group and a group Y¹ as defined hereinbeforein formula XIX, and Z³ has the meaning in formula I, with an appropriateBronsted base and, when the Bronsted base does not contain a hydroxylion, in the presence of water. Examples of appropriate Bronsted basesare alkali and alkaline earth metal oxides and hydroxides for producingcorresponding alkali and alkaline earth metal salts of formula I.Preferably the reaction is effected with heating.

Salts of formula I may be isolated from a reaction medium by anyconventional process for the isolation of salts from a solution thereofin a polar medium. Thus the salts may be isolated by precipitation ofthe salt or by removal of the polar medium.

Precipitation of the salt may be effected by mixed solventcrystallisation or by the addition of excess of base or salt thereof soas to produce a concentration of the cation of the salt to be isolated,substantially in excess of the molar ratio thereof in said salt to beisolated.

Mixed solvent crystallisation may be effected by addition, to a solutionof a salt of formula I in a polar medium, of a second solvent misciblewith the solvent already present and in which second solvent the salt offormula I is less soluble than in the solvent already present.

Removal of the polar medium may be effected by evaporation, for example,by freeze-drying, or by azeotropic distillation.

Desirably the salts of formula I are purified prior to incorporation ina pharmaceutical composition. Purification may be effected by anyconventional method. A particularly valuable purification processcomprises isolation of a crude solid salt of formula I from a reactionmixture wherein said salt has been produced, by any method for theisolation of salts of formula I as described hereinabove; treatment ofan aqueous solution of salt with hydrochloric acid; recovery of thecorresponding acid of formula I as solid; neutralisation of the acid offormula I with Bronsted base of which base the cation is the cation ofthe required salt of formula I; removal of solid impurities byfiltration; and isolation of the salt of formula I by a method asdescribed hereinabove.

Conveniently a carboxylic acid of formula I may be purified prior toneutralisation, by recrystallisation or by isolation of aN,N-dimethylformamide adduct and subsequently heating the adduct todrive off the N,N-dimethylformamide. Recrystallisation may be effectedusing a polar organic solvent optionally containing water, for example,aqueous dimethylformamide, aqueous acetone, or acetic acid may be used.

Esters and amides of acids of formula (I) may be prepared by anyconventional method including esterification of the acid or acidchloride with an alkyl or aryl alcohol to yield the corresponding alkylor aryl ester respectively and reaction of the acid or acid chloridewith ammonia or an amine to yield the corresponding amide or substitutedamide respectively. Compounds of formula (I) where Z¹ and Z² aredifferent and are chosen from acid, ester, amide and salt functions, maybe prepared by the above methods, and by partial hydrolysis, whereappropriate.

The compounds of formula (I) are useful in the treatment or prophylaxisof mammalian allergic conditions such as asthma and other allergic chestconditions, hay fever (allergic rhinitis), conjunctivitis, urticaria andeczema. In particular they are of value in reaginic mediated Type Ihypersensitivity asthma (`extrinsic asthma`) and the so-called`intrinsic asthma` in which no sensitivity to extrinsic antigen can beshown.

The magnitude of a prophylactic or therapeutic dose of compound offormula (I) will of course vary with the nature and the severity of theallergic condition to be treated and with the particular compound offormula (I) and its route of administration. In general the dose rangelies within the range of 2μg. to 100mg. per kg. body weight of a mammal.

In the case of an allergic condition as defined hereinbefore, forexample, allergic asthma, a suitable dosage is from 5μg. to 0.5mg.,preferably from 20μg. to 0.2mg., for example about 0.1mg., of a compoundof formula (I), per kg. of bodyweight of the patient undergoingtreatment, when pulmonary administration as described hereinafter isemployed. In the case where a composition for intravenous administrationis employed a suitable dosage range is from 0.2 to 10mg. (preferably 1to 5mg.) of a compound of formula (I) per kg. of bodyweight of patient,and in the case where an oral composition is employed a suitable dosagerange is about 30mg/kg, e.g. 1 to 50mg. of a compound of formula (I) perkg. of bodyweight of a patient, preferably from 10 to 40mg/kg.

In the case where a composition for nasal and ocular administration isemployed, for example, in the treatment of allergic rhinitis, a suitabledose is from 0.5 to 25mg. of a compound of formula (I) per patient.

The pharmaceutical compositions of the present invention comprise acompound of formula (I) as an active ingredient, and may also containpharmaceutically acceptable carrier and optionally other therapeuticingredients. The compositions include compositions suitable for oral,rectal, opthalmic, pulmonary, nasal, dermal, topical, or parenteral(including subcutaneous, intramuscular and intravenous) administration,although the most suitable route in any given case will depend on thenature and severity of the condition being treated, and on the nature ofthe active ingredient. They may be conveniently presented in unit dosageform and prepared by any of the methods well known in the art ofpharmacy.

Pharmaceutical compositions of the present invention suitable for oraladministration may be presented as discrete units such as capsules,cachets or tablets each containing a predetermined amount of the activeingredient; as a powder or granules; or as a solution or a suspension inan aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or awater-in-oil liquid emulsion. Such compositions may be prepared by anyof the methods of pharmacy but all methods include the step of bringinginto association the active ingredient with the carrier whichconstitutes one or more accessory ingredients. In general thecompositions are prepared by uniformly and intimately admixing theactive ingredient with liquid carriers or finely divided solid carriersor both, and then, if necessary, shaping the product into the desiredpresentation. For example a tablet may be prepared by compression ormoulding, optionally with one or more accessory ingredients. Compressedtablets may be prepared by compressing in a suitable machine, the activeingredient in a free-flowing form such as a powder or granules,optionally mixed with a binder, lubricant, inert diluent, lubricating,surface active or dispersing agent. Moulded tablets may be made bymoulding in a suitable machine, a mixture of the powdered compoundmoistened with an inert liquid diluent. Desirably, each tablet containsfrom 50mg to 500mg of the active ingredient, and each cachet or capsulecontains from 50 to 500mg of the active ingredient.

A particularly valuable form of a pharmaceutical composition of thepresent invention, for use in the treatment of allergic asthma, is acomposition suitable for pulmonary administration via the buccal cavity;although of course conditions other than allergic asthma may also betreated by pulmonary administration of the composition.

Preferably the composition is such that particles having a diameter of0.5 to 7μ most preferably 1 to 6μ, containing active ingredient, aredelivered into lungs of a patient. This ensures that a maximal amount ofactive ingredient is administered to the alveolar sacs of the lungs andretained therein thus producing a maximal effect in the patient. Suchcompositions are most preferably in the form of dry powders foradministration from a powder inhalation device or self-propellingpowder-dispensing compositions.

Most preferably the powders of the pulmonary compositions as describedhereinabove and hereinbelow comprise particles containing activeingredient of which particles at least 98% by weight have a diametergreater than 0.5μ and at least 95% by number have a diameter less than7μ. Most desirably at least 95% by weight of the particles have adiameter greater than 1μ and at least 90% by number of the particleshave a diameter less than 6μ.

The compositions in the form of dry powders preferably compriseparticles containing the solid active ingredient, the particles having adiameter of 0.5 to 7μ most preferably 1 to 6μ. Preferably thesecompositions include a solid diluent in the form of a fine powder. Thesecompositions may be conveniently presented in a pierceable capsule of apharmaceutically acceptable material, for example gelatin. Suchcompositions may be conveniently prepared by comminution of solid activeingredient optionally with a solid diluent. If desired the resultingpowder may be filled into a pierceable capsule of a pharmaceuticallyacceptable material.

Other valuable forms of a composition of the present invention that aresuitable for pulmonary administration are self-propelling compositions.These self-propelling compositions may be either powder-dispensingcompositions or compositions dispensing the active ingredient in theform of droplets of a solution or suspension.

Self-propelling powder-dispensing compositions preferably comprisedispersed particles of solid active ingredient, having a diameter of 0.5to 7μ most preferably 1 to 6μ and a liquid propellant having a boilingpoint of below 65° F. at atmospheric pressure. The liquid propellant maybe any propellant known to be suitable for medicinal administration andmay comprise one or more lower alkyl hydrocarbons, or halogenated loweralkyl hydrocarbons, or mixtures thereof. Chlorinated and fluorinatedlower alkyl hydrocarbons are especially preferred as propellant.Generally the propellant may constitute 50 to 99.9% w/w of thecomposition whilst the active ingredient may constitute 0.1 to 20% w/w,for example, about 2% w/w, of the composition.

The pharmaceutically acceptable carrier in such self-propellingcompositions may include other constituents in addition to thepropellant, in particular a surfactant or a solid diluent or both.Surfactants are desirable in preventing agglomeration of the particlesof active ingredient and in maintaining the active ingredient insuspension. Especially valuable are liquid non-ionic surfactants andsolid anionic surfactants or mixtures thereof. Suitable liquid non-ionicsurfactants are those having a hydrophile-lipophile balance (HLB, seeJournal of the Society of Cosmetic Chemists Vol. 1 pp. 311-326 (1949))of below 10, in particular esters and partial esters of fatty acids withaliphatic polyhydric alcohols, for instance, sorbitan monooleate andsorbitan trioleate, known commercially as `Span 80` (Trade Name) and"Span 85" (Trade Name). The liquid non-ionic surfactant may constituteup to 20% w/w of the composition, though preferably it constitutes below1% w/w of the composition. Suitable solid anionic surfactants includealkali metal, ammonium and amine salts of dialkyl sulphosuccinate, wherethe alkyl groups have 4 to 12 carbon atoms, and alkylbenzene sulphonicacid where the alkyl group has 8 to 14 carbon atoms. The solid anionicsurfactants may constitute up to 20% w/w of the composition, thoughpreferably below 1% w/w of the composition.

Solid diluents may be advantageously incorporated in suchself-propelling compositions where the density of the active ingredientdiffers substantially from the density of the propellant; also in orderto help to maintain the active ingredient in suspension. The soliddiluent is in the form of a fine powder, preferably having a particlesize of the same order as that of the particles of active ingredients.Suitable solid diluents include sodium choride and sodium sulphate.

Compositions of the present invention may also be in the form of aself-propelling composition wherein the active ingredient is present insolution. Such self-propelling compositions may comprise an activeingredient, propellant and co-solvent, and advantageously an antioxidantstabiliser. The propellant is one or more of those already cited above.Co-solvents are chosen for their solubility in the propellant, theirability to dissolve the active ingredient, and for their having thelowest boiling point consistent with these above-mentioned properties.Suitable co-solvents are lower alkyl alcohols and ethers and mixturesthereof. The co-solvents may constitute 5 to 40% w/w of the composition,though preferably less than 20% w/w of the composition.

Antioxidant stabilisers may be incorporated in suchsolution-compositions to inhibit deterioration of the active ingredientand are conveniently alkali metal ascorbates or bisulfites. They arepreferably present in an amount of up to 0.25% w/w of the composition.

Such self-propelling compositions may be prepared by any method known inthe art. For example the active ingredient either as particles asdefined hereinbefore in suspension in a suitable liquid or in up to 20%w/v solution in an acceptable co-solvent as appropriate, is mixed withany other constituents of a pharmaceutically acceptable carrier. Theresulting mixture is cooled and introduced into a suitable cooledcontainer and propellant is added thereto in liquid form; and thecontainer is sealed.

Alternatively, such self-propelling compositions may be prepared bymixing the active ingredient either in particles as hereinbefore definedor in 2 to 20% w/v alcohol or aqueous solution as appropriate, togetherwith the remaining constituents of the pharmaceutically acceptablecarrier other than propellant; introducing the resulting mixture,optionally with some propellant, into a suitable container, sealing thecontainer; and injecting propellant under pressure into the container atambient temperature through a valve which comprises a part of thecontainer and is used to control release of the composition from it.Desirably the container is purged by removing air from it at aconvenient stage in the preparation of the self-propelling composition.

A suitable container for a self-propelling composition, is one providedwith a manually operable valve and being constructed of aluminum,stainless steel or reinforced glass. The valve should of course be onehaving the desired spray characteristic, that is, the spray issuing fromthe valve should have the characteristics of particle size ashereinbefore defined. Advantageously the valve is of the metered type,that is a valve of the type which delivers a fixed amount of compositionon the occasion of each operation of the valve, for example, about 50 or100 microliters of composition in each delivery.

Compositions of the present invention may also be in the form of aqueousor dilute alcholoic solution, optionally a sterile solution, of theactive ingredient for use in a nebuliser or atomiser, wherein anaccelerated air stream is used to produce a fine mist consisting ofsmall droplets of the solution. Such compositions usually contain aflavouring agent such as saccharin sodium and a volatile oil. Abuffering agent such as sodium phosphate; an antioxidant such as sodiummetabisulfite; and a surface active agent may also be included in such acomposition. Desirably such a composition should contain a perservativesuch as methylhydroxybenzoate.

Compositions of the present invention suitable for parenteraladministration conveniently comprise sterile aqueous solutions of theactive ingredient, which solutions are preferably isotonic with blood ofa patient under treatment. These are preferably administeredintra-venously, although adminstration may also be effected by means ofa subcutaneous or intra-muscular injection. Such compositions may beconveniently prepared by dissolving solid active ingredient in water toproduce an aqueous solution, and rendering said solution sterile andisotonic with human blood.

Pharmaceutical compositions of the present invention suitable fortopical use include compositions suitable for administration to theskin, eyes, nose and mouth.

Compositions for use on the skin include lotions and creams comprisingliquid or semi-solid emulsions, either oil-in-water or water-in-oil,which preferably contain from 0.2 to 5% w/v of the active ingredient.Ointments comprising 0.2 to 5% w/v of the active ingredient dissolved ordispersed in a semi-solid basis may also be used for topicaladministration to the skin. Conveniently the semi-solid basis containsliquid or semi-solid hydrocarbons, animal fat, wool alcohol or amacrogol, possibly with an emulsifying agent. Desirably the creams andointments should contain a preservative such as methyl hydroxybenzoate.

Compositions for administration to the eye include eye drops comprisingthe active ingredient in aqueous or oily solution, preferably at aconcentration of 0.2 to 5% w/v. Such solutions are desirably fungistaticand bacteriostatic and are preferably prepared sterile. Compositions foradministration to the eye also include eye ointments which preferablycomprise the same concentration of active ingredient, conveniently inthe form of a salt, either dissolved in one of the ingredients of thesemi-solid basis of the ointment or as a finely divided suspensiontherein.

Compositions suitable for administration to the nose include powder,self-propelling and spray compositions similar to those alreadydescribed under compositions suitable for pulmonary administration buthaving when dispersed, a somewhat larger particle size of the order of10 to 200 microns. In the case of self-propelling solution and spraycompositions this effect may be achieved by choice of a valve having thedesired spray characteristic i.e. being capable of producing a sprayhaving the desired particle size or by incorporating the medicament as asuspended powder of controlled particle size. Thus the compositioninstead of passing into the lungs is largely retained in the nasalcavity. Other compositions suitable for nasal administration include acoarse powder having a particle size of 20 to 500 microns which isadministered in the manner in which snuff is taken i.e. by rapidinhalation through the nasal passage from a container of the powder heldclose up to the nose. Another composition suitable for nasaladministration is nasal drops comprising 0.2 to 5% w/v of the activeingredient in aqueous or oily solution.

Compositions suitable for topical administration in the mouth includelozenges comprising 10 to 100mg. of the active ingredient in a flavouredbasis, usually sucrose and acacia or tragacanth; and pastillescomprising 10 to 100mg. of the active ingredient in an inert basis suchas gelatin and glycerin; or sucrose and acacia.

Other therapeutic ingredients suitable for inclusion in the hereinbeforedescribed compositions, especially in the case of those compositionsintended for use in the treatment of allergic asthma, includebronchodilators. Any bronchodilator may be used in such a compositionalthough particularly suitable bronchodilators are isoprenaline,adrenaline, orciprenaline, isoethanine and physiologically acceptableacid addition salts thereof, especially isoprenaline sulphate.Conveniently the bronchodilator is present in the composition in anamount of 0.1 to 50% w/v of the weight of active ingredient present.

Included within the scope of the present invention, but in no waylimited thereto, are the following specific features:

1. 3-Carboxythioxanthone-10,10-dioxide salts.

2. 3-(5-Tetrazolyl)thioxanthone-10,10-dioxide and salts thereof.

3. A compound of formula I as defined hereinabove, where novel.

4. The synthesis of compounds of formula I as defined hereinabove, byany method known in the art for preparing them and compounds ofanalogous chemical structure.

5. Pharmaceutical compositions comprising a compound of formula I asdefined hereinabove in association with a pharmaceutically accceptablecarrier therefor.

6. The preparation of pharmaceutical compositions comprising a compoundof formula I as defined hereinabove as an active ingredient, by anyconventional method, including admixture of the ingredients.

7. A method of treatment or prophylaxis of mammalian allergic conditionscomprising administration of a therapeutic or prophylactic doserespectively, of a compound of formula I as defined hereinabove.

8. Substantially pure solid 3-carboxythioxanthone-10,10-dioxide having amelting point of at least 287° C.

The following preparations and examples illustrate the methods forpreparing compounds in accordance with the present invention, as well ascompounds and compositions of the present invention. In the examples andpreparations, all temperatures are in degrees Celsius. Where meltingpoints are not given for compounds of formula I, the compounds decomposeat temperatures below their melting points and/or their melting pointsare at temperatures above those readily determinable by conventionaltechniques. In these preparations and examples, the numbering ofsubstituent positions in the tricyclic nucleus used is not necessarilythe same as that used in formula I, but is the standard numbering inrespect of the particular tricyclic nucleus concerned, as given in the"Ring Index", IInd Edition, Published by The American Chemical Society,1960. This standard numbering also applies in respect of the individualnamed compounds disclosed hereinbefore.

Reference Preparation 1-3-Carboxythioxanthone-10,10-dioxide A.Preparation of 2,5-dimethyl diphenyl sulphone

To a mixture of benzene sulphonyl chloride (redistilled) (100.0 g.) andp-xylene (260 ml), vigorously stirred and heated to 40° C., was addedaluminium chloride (135 g.) portionwise over 20 minutes. The temperatureof the reaction was kept between 55° and 60° C. during the addition bymeans of an ice-bath. The reaction was maintained at 60° C. for afurther 45 minutes, cooled and decomposed with ice and concentratedhydrochloric acid. The product separated from the organic layer as ayellow solid. This was filtered off, washed with water, andrecrystallised from methanol. The resulting solid was collected byfiltration, washed with a little cold methanol, and dried at 95° C. togive 2,5-dimethyl diphenyl sulphone melting point 111° C.

B. Preparation of diphenyl sulphone-2,5-dicarboxylic acid

2,5-Dimethyl diphenyl sulphone (106 g.), concentrated nitric acid (400ml) and distilled water (400 ml) were placed in a stainless steelautoclave, sealed, stirred and heated to 160° C. for a total of 5 hours.The internal pressure rose to ca. 75 atmospheres. After cooling, thecrystalline product was collected by filtration, washed well with water,and dried at 100° C. The resulting diphenyl sulphone-2,5-dicarboxylicacid had a melting point of 270°-274° C.

C. Preparation of 3-carboxythioxanthone-10,10-dioxide

Diphenyl sulphone-2,5-dicarboxylic acid (156.8 g.) was stirred withtetraphosphoric acid (ca. 3,300 g.) and phosphorus pentoxide (ca. 330g.) at 220 to 230° C. for 20 minutes, cooled, and poured onto ice-waterwith stirring. The precipitated solid was filtered off under suction,washed well with water and dried at 100° C. The total product wasrecrystallised from aqueous dimethyl formamide, filtered at the boil.The product separated as beige crystals. These were first dried at 100°C., then under vacuum at ca. 170° C., to give 3-carboxythioxanthone-10,10-dioxide having a melting point of 287°-289° C.

Reference Preparation 2 - 2-Carboxythioxanthone-10,10-dioxide A.Preparation of diphenylsulphone-2,4-dicarboxylic acid

Diphenylsulphone-2,4-dicarboxylic acid was obtained (in the mannerdescribed above in preparation 1B by the method used fordiphenyl-2,5-dicarboxylic acid) as colourless needles from water, m.p.246° C.

B. Preparation of 2-Carboxythioxanthone-10,10-dioxide

Diphenylsulphone-2,4-dicarboxylic acid (10.5 g) was stirred and heatedwith polyphosphoric acid (200 g) at 210°-220° C. for 15 minutes, cooled,and poured into water. On heating the mixture to 80° C. the crudeproduct separated and was filtered off and recrystallised from aceticacid, m.p. 276° C.

Reference Preparation 3 - 2-Carboxythioxanthone-10,10-dioxide A.Preparation of methylthioxanthone (isomer mixture)

To a stirred mixture of concentrated sulphuric acid (300 ml) and toluene(46 ml), o-mercaptobenzoic acid (30 g) was added slowly. The mixture wasstirred for 8 hrs. and allowed to stand for a further 10 hrs. After 1hr. heating on the steam bath the dark red solution was cooled andpoured on to ice. The gummy yellow precipitate was filtered off andtriturated with 2N aqueous sodium hydroxide. The solid isomer-mixturewas filtered off, washed with water, and dried at room temperature invacuo, m.p. 107°-132° C.

B. Preparation of 2-methylthioxanthone-10,10-dioxide

To the methylthioxanthone isomer mixture (30.3 g) dissolved in warmacetic acid (200 ml) was added 30% hydrogen peroxide (50 ml), and themixture boiled under reflux for 2.5 hr. On cooling a yellow solidcrystallised out, which was filtered off and dried at 110° C m.p.179°-198° C. Recrystallisation from acetic acid gave pure2-methylthioxanthone- 10,10-dioxide, m.p. 201°-203° C.

C. Preparation of 2-carboxythioxanthone-10,10-dioxide

A solution of chromium trioxide (1.50 g) in water (4.0 ml) was added to2-methylthioxanthone-10,10-dioxide (1.29 g) in acetic acid (25 ml).Sulphuric acid (2.0 ml) was added and the mixture was boiled underreflux for 15 min. The mixture was cooled, and the crystallised productwas filtered off, washed with water, and dried at 110° C., m.p. 276° C.

Reference Preparation 4-3-Carboxythioxanthone-10,10-dioxide A.Preparation of phenylthioterephthalonitrile

To a sodium methoxide solution, prepared by dissolving sodium (1.46 g)in dry methanol (40 ml), was added redistilled thiophenol (6.9 2 g), andthe methanol removed on a rotary evaporator. Dimethyl sulphoxide (50 ml)was added, and to the resulting solution nitroterephthalonitrile (10.38g) was added. The dark brown solution was heated on the steam bath for 2hours, then poured on to ice. The precipitated product was filtered offand dried in vacuo at room temperature, m.p. 106° C. Recrystallisationfrom ethanol gave the pure product, m.p. 110° C.

B. Preparation of phenylthioterephthalic acid

A mixture of phenylthioterephtalonitrile (6.73 g), sodium hydroxide(4.20 g), water (15 ml) and ethanol (100 ml) was boiled under reflux. Asevolution of ammonia began, sodium salts began to precipitate and waterwas added to the reaction mixture to keep the salts in solution. After 2hours the ethanol was allowed to distil off as more water was added to150 ml, the solution was filtered, and poured on to ice and excesshydrochloric acid. The precipitated product was filtered off, washedwith water, and dried at 110° C., m.p. 328°-331° C.(sublines).

C. Preparation of thioxanthone-3-carboxylic acid

Phenylthioterephthalic acid (7.10 g) was heated with polyphosphoric acid(50 g) at 210°-215° C. for 2 hrs. With occasional stirring. The darkmixture was poured into water and heated to boiling point, and thegreenish product filtered off, washed with water, and recrystallisedfrom aqueous dimethylformamide, m.p. 314°-315° C. and a second crop ondilution of the half-evaporated acetic acid liquors with water, gave am.p. 313°-314° C.

D. Preparation of 3-carboxythioxanthone-10,10-dioxide

A mixture of thioxanthone-3-carboxylic acid (0.120 g), acetic acid (6.0ml) and 30% hydrogen peroxide (0.12 ml) was boiled under reflux for 15hr. filtered while hot, and allowed to cool. The product crystallisedout slowly. It was filtered off and dried at 110° C., m.p. 285°-287° C.

Reference Preparation 5 - 3-Carboxythioxanthone-10,10-dioxide

To 3-carboxythioxanthone-10,10-dioxide (0.72 g) (prepared as hereinafterdescribed) in pyridine (20 ml) was added 40% Triton B pyridine solution(3.5 ml), which resulted in the formation of a deep orange colour. Airwas passed through the solution for 20 minutes, after which time thesolution was pale green. During the reaction interruption of the airflow resulted in the development of a deep blue colour which disappearedwhen the flow was restarted. This did not occur when the reaction wascompleted. The solution was poured onto ice and excess hydrochloric acidand the pale yellow product filtered off and dried at 110° C., m.p.257°-267° C. After two recrystallisations from acetic acid the producthad a m.p. of 282°-284° C. and its infra-red spectrum was identical withthat of an authentic sample of 3-carboxythioxanthone-10,10-dioxide.

Reference Preparation 6 - 2,6-Dicarboxythioxanthone-10,10-dioxide

To stirred polyphosphoric acid (800 g) at 290° C. was added diphenylsulphone 2,4',5-tricarboxylic acid (56.7 g) (Bennett, Can. J. Chem., 431880 (1965); and Bennett and Gauvin, J. Org. Chem., 34 4165 (1969)) andthe temperature maintained at 290° C. for 1/2 hour. The mixture wascooled, and decomposed by heating with water. The black solid wasfiltered off and recrystallised twice from dimethyl formamide, m.p.above 400° C.

Reference Preparation 7 - 3-Carboxythioxanthone-10,10-dioxide

3-Carboxythioxanthone-10,10-dioxide (prepared as in ReferencePreparation 1) (5.0 g), zinc wool (10.0 g) and mercuric acetate (0.2 g)in acetic acid (100 ml) were brought to the boil and concentratedhydrochloric acid (10 ml) was added. Vigorous evolution of hydrogenchloride occurred at first. After 2 hrs., further hydrochloric acid (7ml), was added and the mixture boiled under reflux for further 4 hrs. Itwas then filtered while hot and poured on to ice and water. Theprecipitated product was filtered off and dried at 80° C. in vacuo, m.p.229°-248° C. Two recrystallisations from methanol gave the product m.p.254° C.

EXAMPLE 1 2,7-Dicarboxythioxanthone-10,10-dioxide A. Preparation of2,4,4'-Trimethyldiphenyl sulphone

To a stirred mixture of anhydrous aluminium chloride (66.6g.) inm-xylene (100 ml.) at 50° C. was added a solution of p-toluene-sulphonylchloride (50g.) in m-xylene (60 ml.), dropwise. The temperature of thereaction mixture was allowed to rise to 80° C. over 1.5 hrs. by externalheating, then the mixture was cooled and poured on to ice andhydrochloric acid. The excess xylene was steam-distilled out and theoily product extracted into chloroform, washed with water and sodiumbicarbonate solution, dried, and evaporated. Vacuum distillation gave2,4,4'-trimethyldiphenyl sulphone, b.pt. 181° C. at 0.5 mm.Hg.

B. Preparation of Diphenyl sulphone-2,4,4'-tricarboxylic acid

2,4,4'-Trimethyldiphenyl sulphone (32.0g.) was heated with 35% nitricacid (200 ml.) in an autoclave to 175° C. over 1.5 hrs. This temperaturewas maintained for a further 0.75 hr. After cooling the solid productwas filtered off, washed with water, recrystallised from aqueousdimethylformamide, and dried at 110° C., giving diphenylsulphone-2,4,4'-tricarboxylic acid m.pt. 352°-353° C. withdecomposition.

Found: C 51.47%; H 3.04%; S 8.98%. C₁₅ H₁₀ O₈ S requires: C 51.44%; H2.88%; S 9.15%.

C. Preparation of 2,7-Dicarboxythioxanthone-10,10-dioxide

Diphenyl sulphone-2,4,4'-tricarboxylic acid (8.50g.) was heated withpolyphosphoric acid (127g.) at 290° C. for 0.5 hr. with stirring. Thedark syrup was cooled and decomposed with water overnight. The darksolid product was filtered off and recrystallised twice fromdimethylformamide to give 2,7-dicarboxythioxanthone-10,10-dioxide, m.pt.372°-375° C. with decomposition.

Found: C 54.15%; H 2.47%; S 9.51%. C₁₅ H₈ O₇ S requires C 54.24%; H2.43%; S 9.65%.

EXAMPLE 2 3-Methoxycarbonylthioxanthone-10,10-dioxide.

3-Carboxythioxanthone-10,10-dioxide (2.0g.), thionyl chloride (25 ml.),and dimethylformamide (2 drops) were boiled together under reflux for 1hr. The solution was evaporated to dryness, and methanol (100 ml.)added. The mixture was heated to boiling and the clear solution filteredand allowed to cool. The product, which crystallised out, was filteredoff and recrystallised from methanol to give3-methoxycarbonyl-thioxanthone-10,10-dioxide, m.pt. 145° - 146° C.

Found: C 59.77., H 3.31%. C₁₅ H₁₀ O₅ S requires C 59.60%; H 3.33%.

EXAMPLE 3 3-Carboxy-7-ethylthioxanthone-10,10-dioxide A.p-Ethylthiophenol

Chlorosulphonic acid (180 g) was added with stirring to ethylbenzene (36g) at 10° C. This temperature was maintained by external coolingthroughout the addition. When the addition was completed the mixture waspoured on to ice and the product extracted into ether. The combinedextracts were washed with water, dried with magnesium sulphate andevaporated.

The residual sulphonyl chloride was stirred with 25% sulphuric acid (500ml) at 0°-5° C. while zinc dust (70 g) was added. The mixture was thenheated slowly, and at 88° C. an exothermic reaction began. Thetemperature rose until the mixture boiled gently, and the yellow, oilyproduct detached itself from the zinc. It was steam distilled out,extracted into methylene chloride, dried, evaporated and distilled togive p-ethylthiophenol, b.p. 93°-98° C. at 12 mm.Hg.

B. 2-(p-Ethylphenylthio)terephthalic acid

Sodium (2.0 g) was dissolved in methanol (60 ml) and p-ethylthiophenol(10.0 g) added. The solution was evaporated to dryness and the residuedissolved in dimethylsulphoxide (60 ml). Nitroterephthalonitrile (12.32g) was added and the mixture heated on the steam bath for 3 hours. Themixture was poured onto ice and the crude product extracted into ether.The extracts were evaporated and boiled under reflux with a solution ofsodium hydroxide (9.0 g) in water (250 ml) for 16 hours. The solutionwas cooled and extracted with ether to remove some unchanged thiol, andthe aqueous solution was poured into excess hydrochloric acid. Theprecipitated product was filtered off, washed with hot water, and driedat 95° C. in vacuo, giving 2-(p-ethylphenylthio)terephthalic acid. Asample recrystallised from acetic acid decomposed without melting, andwas microanalysed:

Found: C 63.33%; H 4.80%; C₁₆ H₁₄ O₄ S requires: C 63.56%; H 4.67%

C. 7-Ethylthioxanthone-3-carboxylic acid

2-(p-Ethylphenylthio)terephthalic acid (19.0 g) was heated withconcentrated sulphuric acid (150 ml) at 120° C. for 1.5 hours. Thesolution was cooled and poured on to ice. The product was filtered off,washed with water, and recrystallised from acetic acid giving7-ethylthioxanthone-3-carboxylic acid, m.p. 261°-271° C. A sample wasfurther purified by conversion to the acid chloride. The acid (1.09 g)was boiled with thionyl chloride (ca. 10 ml) for 1 hour and the excessthionyl chloride was evaporated off. The residual acid chloride wasrecrystallised from toluene, then hydrolysed by boiling with excesssodium hydroxide. Acidification gave the acid, which was recrystallisedfrom acetic acid and dried at 156° C. in vacuo, m.p. 276°-284° C., pureby thin layer chromatography.

Found: C 67.51%; H 4.23%. C₁₆ H₁₂ O₃ S requires C 67.59%; H 4.25%.

D. 3-Carboxy-7-ethylthioxanthone-10,10-dioxide

7-Ethylthioxanthone-3-carboxylic acid (0.25g), 30% hydrogen peroxide(0.25 ml) and acetic acid (2.5 ml) were mixed and boiled under refluxfor 4 hrs. Further acetic acid was added to completely dissolve theproduct and the boiling solution was filtered and cooled.3-Carboxy-7-ethylthioxanthone-10,10-dioxide crystallised out and wasfiltered off and dried m.p. 300° - 303° C.

Found: C 60.55%, H 3.85%. C₁₆ H₁₂ O₅ S requires C 60.76%; H 3.82%.

EXAMPLE 4 7-Ethyl-3-(5-tetrazolyl)thioxanthone-10,10-dioxide A.3-Cyano-7-ethylthioxanthone

7-Ethylthioxanthone-3-carboxylic acid (6.07g) was boiled under reflux inthionyl chloride (40ml) containing dimethylformamide (1 drop). Thethionyl chloride was distilled off and the residual acid chloridetreated with 0.880 ammonia (140 ml). The mixture was boiled for 20minutes, cooled, and the amide filtered off and dried. To a solution ofthe amide in dimethylformamide (100 ml) cooled to -30° C. was addedthionyl chloride (15 ml) in small portions with cooling. When theaddition was complete the mixture was allowed to stand at 0° C. for 20min., poured into water, and the crude 3-cyano-7-ethylthioxanthonefiltered off and dried, m.p. 198°-215° C. A sample recrystallised fromacetic acid had m.p. 210°-216° C.

B. 7-Ethyl-3-(5-tetrazolyl)thioxanthone

3-Cyano-7-ethylthioxanthone (5.3 g), sodium azide (1.55 g), and ammoniumchloride (1.26 g) in dimethylformamide were heated at 120° C. for 3hours, cooled, and poured into dilute hydrochloric acid. The solidprecipitate was filtered off and recrystallised twice from acetic acidto yield 7-ethyl-3-(5-tetrazolyl)thioxanthone m.p. 247° C. withdecomposition.

Found: C 61.92%; H 4.05%; N 18.18%; C₁₆ H₁₂ N₄ OS requires C 62.32%; H3.92%; N 18.17%.

C. 7-Ethyl-3-(5-tetrazolyl)thioxanthone-10,10-dioxide

7-Ethyl-3-(5-tetrazolyl)thioxanthone (1.0 g) in acetic acid (10 ml) and30% hydrogen peroxide (1.0 ml) were boiled under reflux for 2 hours. Oncooling, 7-ethyl-3-(5-tetrazolyl)thioxanthone-10,10-dioxide (0.76 g)crystallised out and was filtered off and dried, m.p. 239° C. withdecomposition.

Found: C 56.46%; H 3.55%; N 16.46%: C₁₆ H₁₂ N₄ O₃ S requires C 56.21%; H3.66%; N 16.47%.

EXAMPLE 5 7-tert. Butyl-3-carboxythioxanthone-10,10-dioxide A.2-(p-tert. Butylphenylthio)terephthalic acid

Starting from p-tert.-butylthiophenol (8.30 g) andnitroterephthalonitrile (8.65 g), 2-(p-tert-butylphenylthio)terephthalicacid (5.23 g), m.p. 325°-326° C., was prepared in the same way as theethyl analogue.

Found: C 65.64%; H 5.83%; C₁₈ H₁₈ O₄ S requires: C 65.43%; H 5.49%

B. 7-tert.-Butylthioxanthone-3-carboxylic acid

2-(p-tert.-Butylphenylthio)terephthalic acid (5.23 g) was cyclised byheating with concentrated sulphuric acid (50 ml) on the steam bath for10 hours. The solution was cooled and diluted with water, and theprecipitated product filtered off and recrystallised from ethanol,giving 7-tert.-butylthioxanthone-3-carboxylic acid m.p. 252°-257° C. Asample recrystallised from toluene followed by a furtherrecrystallisation from acetic acid had a m.p. of 259°-261° C.

Found: C 69.30%; H 5.20%; C₁₈ H₁₆ O₃ S requires: C 69.21%; H 5.16%.

C. 7-tert.-Butyl-3-carboxythioxanthone-10,10-dioxide

7-tert.-Butylthioxanthone-3-carboxylic acid (1.52 g) in acetic acid (15ml) and 30% hydrogen peroxide (3.0 ml) was boiled under reflux for 2hours. On cooling, 7-tert-butyl-3-carboxythioxanthone-10,10-dioxideseparated and was filtered off and recystallised, once from acetic acidand once from aqueous ethanol, to give m.p. 259°-262° C.

Found: C 62.76%; H 4.69%; C₁₈ H₁₆ O₅ S requires: C 62.78%; H 4.68%.

EXAMPLE 6

7-tert.-Butyl-3-(5-tetrazolyl)thioxanthone-10,10-dioxide

A. 7-tert.-Butylthioxanthone-3-carboxamide

7-tert.Butylthioxanthone-3-carboxylic acid (2.0 g) was boiled underreflux with thionyl chloride (20 ml) for 30 mins. The thionyl chloridewas evaporated off and the residue dissolved in hot toluene (25 ml) anddecanted from a small quantity of tarry impurity. Evaporation gave theacid chloride which was treated with 0.880 ammonia (50 ml), warmed onthe water bath, filtered and washed with water to yield after drying7-tert. butylthioxanthone-3-carboxamide, m.p. 274°-275° C.

B. 7-tert.Butyl-3-cyanothioxanthone

7-tert.Butylthioxanthone-3-carboxamide (1.67 g) was dissolved in hotdimethylformamide (15 ml) and cooled to -60° C. Thionyl chloride (3.0ml) was added and the mixture allowed to warm to 0° C. in an ice bathfor 20 mins., poured into water, and 7-tert.butyl-3-cyanothioxanthonefiltered off and dried, m.p. 181°-184° C.

C. 7-tert.-Butyl-3-(5-tetrazolyl)thioxanthone

A mixture of 7-tert.butyl-3-cyanothioxanthone (1.25 g), sodium azide(0.31 g), ammonium chloride (0.25 g) and dimethylformamide (15 ml) washeated at 125°-130° C. for 4 hours, cooled, and poured into dilutehydrochloric acid. The yellow precipitated product was filtered off andrecrystallised from dimethylformamide to yield7-tert.-butyl-3-(5-tetrazolyl)thioxanthone, m.p. 277° C. withdecomposition.

Found: C 64.33%; H 5.11%; N 16.68%; C₁₈ H₁₆ N₄ OS requires: C 64.27%; H4.80%; N 16.66%

D. 7-tert.-Butyl-3-(5-tetrazolyl)thioxanthone-10,10-dioxide

7-tert.-Butyl-3-(5-tetrazolyl)thioxanthone (1.0 g) was boiled underreflux with acetic acid (10 ml) and 30% hydrogen peroxide (1.0 ml) for 2hours, diluted with water to saturation point at the boil, filtered andcooled. 7-tert.-Butyl-3-(5-tetrazolyl) thioxanthone-10,10-dioxidecrystallised out and was filtered off and recrystallised fromdimethylformamide, m.p. 228° C. with decomposition.

Found: C 58.28%; H 4.47%; N 14.74%. C₁₈ H₁₆ N₄ O₃ S requires: C 58.68%;H 4.38%; N 15.21%

EXAMPLE 7 4-Carboxythioxanthone-10,10-dioxide A. Cupric o-chlorobenzoate

o-Chlorobenzoic acid (31.3 g) was dissolved in a solution of sodiumhydroxide (8.0 g) in water (250 ml) and the warmed solution filtered andtreated with a solution of cupric sulphate pentahydrate (25.0 g) inwater (200 ml). The precipitated bluegreen solid was filtered off,washed with water, and dried to give cupric chlorobenzoate, m.p. 259° C.with decomposition.

B. Cupric complex of thiosalicylic acid

Thiosalicylic acid (30.8 g) was added to a solution of sodium hydroxide(16.0 g) in water (300 ml) and to the resulting solution was added asolution of cupric sulphate pentahydrate (50.0 g) in water (30 ml). Theprecipitated black complex was filtered off, washed with water andethanol, and dried.

C. Diphenyl sulphide 2,2'-dicarboxylic acid

A mixture of cupric o-chlorobenzoate (28. 2g), thiosalicylic acid cupriccomplex (32.4g) and dimethylformamide (450 ml) was boiled under refluxfor 2 hrs. The dull green precipitate was filtered from the cooledmixture and allowed to stand overnight in 2N. hydrochloric acid (200ml). The product was filtered off, washed with water, and heated withnormal sodium hydroxide solution (400 ml). A black residue was filteredoff and the filtrate acidified to precipitate diphenyl sulphide,2,2'-dicarboxylic acid which was filtered off, washed with water anddried, m.p. 232° - 234° C. A sample recrystallised from acetic acid hadm.p. 236° C.

Found: C 61.42%, H 3.72%. C₁₄ H₁₀ O₄ S requires C 61.32%, H 3.68%.

D. Thioxanthone-4-carboxylic acid

Diphenyl sulphide 2,2'-dicarboxylic acid (19.0g) was heated on a steambath with concentrated sulphuric acid (150 ml) for 1 hr., and the darksolution cooled and poured into water. The yellow precipitate wasfiltered off, washed well with water and dried, givingthioxanthone-4-carboxylic acid. A sample recrystallised fromdimethylformamide, then acetic acid, had m.p. 353° C. (withsublimation).

Found: C 65.47%; H 3.14%. C₁₄ H₈ O₃ requires: C 65.74%; H 3.28%.

E. 4-Carboxythioxanthone-10,10-dioxide

Thioxanthone-4-carboxylic acid (5.0g), acetic acid (100 ml) and 30%hydrogen peroxide (5.0 ml) were boiled under reflux for 1 hour. Oncooling, 4-carboxythioxanthone-10,10-dioxide crystallised out and wasfiltered off and dried, m.p. 237° C.

Found: C 58.14%; H 2.95%; C₁₄ H₈ O₅ requires: C 58.34%; H 2.80%.

EXAMPLE 8 4-(5-Tetrazolyl)thioxanthone-10,10-dioxide A.4-Cyanothioxanthone-10,10-dioxide

4-Caroboxythioxanthone-10,10-dioxide (2.10 g) was boiled with thionylchloride (15 ml) containing 1 drop of dimethylformamide for 10 mins.,cooled and evaporated. The residual acid chloride was treated with 0.880ammonia (30 ml) and warmed on a steam bath for 10 mins. The solid amide(1.75 g) was filtered off and dried (m.p. 252°-254° C.). It wasdissolved in hot dimethylformamide (30 ml) and cooled to -70° C. Thionylchloride (4.0 ml) was added and the solution stood in an ice-bath for 30mins. The mixture was poured into cold water and 4-cyanothioxanthonefiltered off, washed with water and dried, m.p. 289°-291° C.

B. 4-(5-Tetrazolyl)thioxanthone-10,10-dioxide

4-Cyanothioxanthone-10,10-dioxide (1.35 g), sodium azide (0.39 g)ammonium chloride (0.32 g) and dimethylsulphoxide were heated togetherat 125°-130° C. for 6.5 hours. The mixture was cooled, poured intodilute hydrochloric acid and the precipitated product filtered off. Itwas warmed with 1% sodium bicarbonate solution, filtered, and thefiltrate acidified with dilute hydrochloric acid.4-(5-Tetrazolyl)thioxanthone-10,10-dioxide was filtered off andrecrystallised from acetic acid, m.p. 271° C. with decomposition.

Found: C 53.50%; H 2.70%; N 18.04%. C₁₄ H₈ N₄ O₃ S requires C 53.85%; H2.58%; N 17.95%.

EXAMPLE 9 3((2-Carboxyethyl)-5-tetrazolyl)thioxanthone-10,10-dioxide

Ethyl 3-bromopropionate (9.05 g) in acetone (70 ml) was added to3-(5-tetrazolyl)thioxanthone-10,10-dioxide (15.6 g) and sodium hydroxide(2.0 g) in water (15 ml). The mixture was boiled under reflux for 8 hr.On cooling the ester product crystallised out and was filtered off,washed with dilute sodium bicarbonate solution, and recrystallised fromethanol, m.p. 143°-145° C. The ester (4.5 g) was boiled with a mixtureof concentrated hydrochloric acid (40 ml) and acetic acid (120 ml) for 3hr. On cooling,3-((2-carboxyethyl)-5-tetrazolyl)thioxanthone-10,10-dioxide crystallisedout and was filtered off and washed with water, m.p. 206°-207° C.

Found: C, 53.10%; H, 3.22%; N, 14.59%. C₁₇ H₁₂ N₄ O₅ S requires C,53.12%; H, 3.15%; N, 14.58%.

EXAMPLE 10 3-(2-Methyl-5-tetrazolyl)thioxanthone-10,10-dioxide

To a solution of sodium ethoxide in ethanol (20 ml) (prepared from 0.46g sodium) was added 3-(5-tetrazolyl) thioxanthone-10,10-dioxide (6.24g).Methyl iodide (2.84 g) was added and the mixture boiled under reflux for2 hrs. During the reflux period a yellow product was deposited. Oncooling it was filtered off, washed with water and recrystallised twicefrom acetic acid to give3-(2-methyl-5-tetrazolyl)thioxanthone-10,10-dioxide as yellow needles,m.p. 204°-205° C.

EXAMPLE 113-(2(3-Dimethylaminopropyl)-5-tetrazolyl)thioxanthone-10,10-dioxide

Sodium (0.69 g) was dissolved in ethanol (45 ml) and3-(5-tetrazolyl)thioxanthone-10,10-dioxide (4.68 g) was added.3-Dimethylaminopropyl chloride hydrochloride (2.37 g) was added to themixture, which was then stirred and boiled under reflux for 2.5 hours.On cooling some solid separated, which was filtered off and discarded.Overnight yellow crystals of3-(2-(3-dimethylaminopropyl)-5-tetrazolyl)thioxanthone-10,10-dioxideseparated and were filtered off and recrystallised from ethanol, m.p.141°-142° C.

Found: C 57.96%; H 5.00%; N 17.58% C₁₉ H₁₉ N₅ O₃ S requires: C 57.41%; H4.82%; N 17.62%.

EXAMPLE 12 3-(2-Carboxymethyl-5-tetrazolyl)thioxanthone-10,10-dioxide

Sodium (0.46 g) was dissolved in ethanol (20 ml) and3-(5-tetrazolyl)thioxanthone-10,10-dioxide (6.24 g) was added. Ethylbromoacetate (3.34 g) was added to the mixture, which was boiled underreflux for 1.5 hours. The ester intermediate was deposited during thistime, and after cooling was filtered off, washed with water and dried,m.p. 194°-195° C. The ester was boiled with concentrated hydrochloricacid (40 ml) and acetic acid (120 ml) for 2 hr. On cooling3-(2-carboxymethyl-5-tetrazolyl)thioxanthone-10,10-dioxide crystallisedout, and was filtered off, recrystallised from acetic acid, and dried,m.p. 252° C. with decomposition.

Found: C, 52.09%; H, 2.73%; N, 15.10%. C₁₆ H₁₀ N₄ O₅ S requires C,51.90%; H, 2.72%; N, 15.13%.

EXAMPLE 13 2-Carboxy-6-(5-tetrazolyl)thioxanthone-10,10-dioxide

7-Methyl-3-(5-tetrazolyl)thioxanthone-10,10-dioxide (0.78g) wassuspended in acetic acid (50 ml) and chromium trioxide (0.98g) in water(2.0 ml) added dropwise, followed by concentrated sulphuric acid (0.5ml) added dropwise. The mixture was heated on the steam bath for 1 hr.,then boiled under reflux for 4 hr. Further chromium trioxide (0.98 g)was added and the mixture boiled for a further 16 hr. The green solutionwas diluted with water, and the precipitated solid filtered off andwashed with water. The solid was boiled with acetic acid (200 ml),filtering at the boil.

Insoluble material (0.26 g) was removed, and on cooling and standing,2-carboxy-6-(5-tetrazolyl)thioxanthone-10,10-dioxide separated. This wasfiltered off, washed with water and dried. The dipotassium salt wasobtained by dissolving the solid in the minimum possible quantity ofwarm saturated potassium bicarbonate solution. On cooling in an ice baththe dipotassium salt trihydrate separated and was filtered off, washedwith a little ice-water and dried.

Found: C, 37.04%; H, 2.24%; N, 11.31%. C₁₅ H₆ K₂ N₄ O₅ S.3H₂ O requires:C, 37.03%; H, 2.47%; N, 11.52%.

EXAMPLE 14 3-Carboxy-7-chlorothioxanthone-10,10-dioxide A.p-Chlorophenylthioterephthalonitrile

Sodium (1.15g) was dissolved in dry methanol (35 ml), andp-chlorothiophenol (7.23g) was added. The solution was evaporated anddimethylsulphoxide (40 ml) added to the residue, followed bynitroterephthalonitrile (8.65g). The solution was heated on a steam bathfor 30 mins., poured into cold water, and the precipitatedp-chlorophenylthioterephthalonitrile filtered off, washed with water,and dried, m.p. 162°-165° C. A sample recrystallised from isopropanolhad m.p. 167°-168° C.

B. p-Chlorophenylthioterephthalic acid

p-Chlorophenylthioterephthalonitrile (8.0g) was boiled under reflux withsodium hydroxide (4.55 g) in water (150 ml) for 16 hr. Filtration of thehot solution gave the diamide, m.p. 308°-310° C., and acidification ofthe filtrate with hydrochloric acid yieldedp-chlorophenylthioterephthalic acid, m.p. 346°-347° C. A samplerecrystallised from acetic acid had m.p. 353°-354° C.

C. p-Chlorophenylsulphonylterephthalic acid

p-Chlorophenylthioterephthalic acid (2.0g), acetic acid (20 ml) and 30%hydrogen peroxide (2.0 ml) were boiled together under reflux for 30 min.Further peroxide (2.0 ml) was added and boiling continued for a further30 min. The solution was partially evaporated, diluted with water, andthe precipitated p-chlorophenylsulphonylterephthalic acid filtered offand recrystallised from aqueous acid m.p. 270°-272° C.

D. 3-Carboxy-7-Chlorothioxanthone-10,10-dioxide

p-Chlorophenylsulphonylterephthalic acid (5.0g) was dissolved inconcentrated sulphuric acid (50 ml) and heated at 240° C. for 2 hr. Thesolution was cooled, poured on to ice, and the precipitated3-carboxy-7-chlorothioxanthone-10,10-dioxide filtered off, washed withwater, and recrystallised from acetic acid, m.p. 352°-355° C.

Found: C, 52.06%; H, 2.16%; C₁₄ H₇ ClO₅ S requires: C, 52.10%; H, 2.19%.

EXAMPLE 15 7-Chloro-3-(5-tetrazolyl)thioxanthone-10,10-dioxide A.2-(p-Chlorophenylthio)-4-(5-tetrazolyl)benzonitrile

p-Chlorophenylthioterephthalonitrile (3.28 g), sodium azide (0.78 g),ammonium chloride (0.65g) and dimethylformamide (30 ml) were heatedtogether on the steam bath for 16 hr. The mixture was cooled and pouredinto dilute hydrochloric acid. The oil which precipitated and solidifiedslowly was dissolved in sodium bicarbonate solution and the solutionextracted with chloroform to remove unchanged starting material.Acidification of the aqueous solution precipitated2-(p-Chlorphenylthio)-4-(5-tetrazolyl)benzonitrile, decomposes at 222°C.

B. 2-(p-Chlorophenylthio)-4-(5-tetrazolyl)benzoic acid

2-(p-Chlorophenylthio)-4-(5-tetrazolyl)benzonitrile (3.24g) wasdissolved in 0.5N sodium hydroxide solution (150 ml) and boiled underreflux for 16 hr. The warm solution was acidified with hydrochloric acidand the precipitated 2-(p-chlorophenylthio)-4-(5-tetrazolyl)benzoic acidfiltered off, washed with water and dried, decomposes at 245° C.

C. 7-Chloro-3-(5-tetrazolyl)thioxanthone

2-(p-Chlorophenylthio)-4-(5-tetrazolyl)benzoic acid (3.41g) was heatedwith polyphosphoric acid (70g) on a steam bath for 1 hr. The reactionmixture was decomposed by warming with water, and the product filteredoff, washed with water, recrystallised from dimethylformamide, and driedat 156° C. in vacuo, giving 7-chloro-3-(5-tetrazolyl)thioxanthone,decomposes without melting.

Found: C, 53.75%; H, 2.27%; N, 17.93%. C₁₄ H₇ ClN₄ OS requires: C,53.42%; H, 2.24%; N, 17.80%.

D. 7-Chloro-3-(5-tetrazolyl)thioxanthone-10,10-dioxide

7-Chloro-3-(5-tetrazolyl) thioxanthone (1.21g), acetic acid (20 ml) and30% hydrogen peroxide (3.5 ml) were boiled together under reflux for 2.5hr. The solid did not pass into solution completely. The mixture wascooled and the solid product filtered off and recrystallised twice fromdimethylformamide to give7-chloro-3-(5-tetrazolyl)thioxanthone-10,10-dioxide, decomposes withoutmelting.

Found: C, 48.65%; H, 2.10%; N, 15.85%. C₁₄ H₇ ClO₃ S requires: C,48.49%; H, 2.03%; N, 16.16%.

EXAMPLE 16 3-Carboxy-7-methoxythioxanthone-10,10dioxide A.p-Methoxyphenylthioterephthalonitrile

Sodium (4.66g) was dissolved in methanol (120 ml) andp-methoxythiophenol (28.3g, prepared by the method used forp-ethylthiophenol) was added. The solution was evaporated to dryness andthe residue dissolved in dimethylsulphoxide (200 ml).Nitroterephthalonitrile (34.9g) was added, and the resulting solutionheated on the steam-bath for 1 hr. On diluting the cooled solution withwater, p-methoxyphenylthioterephthalonitrile crystallised out and wasfiltered off and dried. A sample recrystallised from ethanol had m.p.126°-127° C.

B. p-Methoxyphenylthioterephthalic acid

p-Methoxyphenylthioterephthalonitrile (1.60g), sodium hydroxide (0.91g)and water (30 ml) were boiled together under reflux for 8 hr. A solidresidue was filtered from the reaction mixture and the filtrateacidified with hydrochloric acid. p-Methoxyphenylthioterephthalic acidwas filtered off, washed with water and dried. A sample recrystallisedfrom acetic acid had m.p. 326° C.

C. 7-Methoxythioxanthone-3-carboxylic acid

p-Methoxyphenylthioterephthalic acid (13.4g) was heated withpolyphosphoric acid (260g) at 120° C. for 2 hr., then at 140° C. for 4hr. The reaction mixture was decomposed by warming with water and thesolid product was filtered off and washed well with water.Recrystallisation from acetic acid gave impure7-methoxythioxanthone-3-carboxylic acid, m.p. >360° C.

D. 3-Carboxy-7-methoxythioxanthone-10,10-dioxide

7-Methoxythioxanthone-3-carboxylic acid (1.50g), acetic acid (25 ml) and30% hydrogen peroxide (1.0 ml) were boiled together under reflux for 2hr. Some solid remained undissolved. The mixture was cooled andfiltered, and the residue recrystallised first from acetic acid, thenfrom dimethylformamide to give3-carboxy-7-methoxythioxanthone-10,10-dioxide, m.p. 324° -327° C.

Found: C, 56.33%; H, 3.15%; C₁₅ H₁₀ O₆ S requires: C. 56.61%; H, 3.17%.

EXAMPLE 17 3-(5-Tetrazolyl)thioxanthone-10,10-dioxide sodium salt A.Preparation of 3-Carbamoylthioxanthone-10,10-dioxide

3-Carboxythioxanthone-10,10-dioxide (15.0 g) (prepared as in ReferencePreparation 1) was refluxed with thionyl chloride (100 ml) for 2 hours.The clear solution was evaporated under reduced pressure to give a solidresidue. Carbon tetrachloride was added and re-evaporated, repeatingseveral times, to remove any remaining thionyl chloride. The resultingsolid was added portionwise to aqueous ammonia (75 ml water, 75 ml of.880 ammonia) with stirring, stirred for two hours, and the resultingpink-coloured solid was filtered, washed with water and dried at 100°C., then at 110° C. under vacuum. The resulting3-carbamoylthioxanthone-10,10-dioxide when recrystallised from dimethylformamide had a melting point of 292° C.

B. Preparation of 3-cyanothioxanthone-10,10-dioxide

3-Carbamoylthioxanthone-10,10-dioxide (32.5 g) was dissolved in dimethylformamide (ca. 1 liter) and cooled to -10° C. in a solid carbon dioxideethanol bath. Thionyl chloride (80 ml) was then added dropwise over 0.5hour, maintaining the internal temperature at -5° to -10° C. Stirringwas continued at this temperature for a further 2 hours. The reactionmixture was then poured into ice-water. The precipitated solid wasfiltered off, washed well with water, and dried at 100° C. The resulting3-cyanothioxanthone-10,10-dioxide had a melting point of 282°-283° C.

C. Preparation of 3-(5-tetrazolyl)thioxanthone-10,10-dioxide sodium salt

3-Cyanothioxanthone-10,10-dioxide (28.2 g), sodium azide (7.5 g),ammonium chloride (6.7 g) and dimethylformamide (180 ml) were warmedtogether on a steam bath for a total of 7 hours, left to stand for twodays at room temperature, and then poured onto ice and concentratedhydrochloric acid. The cream-coloured precipitate was filtered off andwarmed with N aqueous sodium hydroxide solution (110 ml) on the steambath. The mixture was filtered from insoluble material, and the filtratedeposited the required product on cooling. This was filtered off, washedwith a little cold water, and dried under vacuum at ca. 90° C., to give3-(5-tetrazolyl)thioxanthone-10,10-dioxide sodium salt) which thendispersed in a potassium bromide disc had the infra-red spectrum shownin FIG. 1. (Unicam SP200 - Unicam Instruments Ltd., Cambridge)

EXAMPLE 18 3-(5-Tetrazolyl)thioxanthone-10,10-dioxide

The sodium salt of Example 17 (2.0 g) was dissolved in distilled water(75 ml) with slight warming. The yellow/orange solution was thenacidified to congo red with 2N hydrochloric acid to precipitate therequired product. This was filtered off, washed with water, andrecrystallised from boiling glacial acetic acid, filtering at the boil.The resulting yellow crystals were collected by filtration, washed witha little cold glacial acetic acid, and finally dried under vacuum at140° C. The product, 3-(5-tetrazolyl)thioxanthone- 10,10-dioxide had amelting point 260°-262° C. (decomposition).

EXAMPLE 19 3-(5-Tetrazolyl)thioxanthone-10,10-dioxide A. Preparation ofthioxanthone-3-carboxamide

Thioxanthone-3-carboxylic acid (3.00 g) (prepared as described herein)was refluxed with thionyl chloride (20 ml) for 45 min. The excessthionyl chloride was evaporated off, and the residual acid chloridedissolved in methylene chloride (70 ml) and added to 0.880 ammoniasolution (70 ml). The precipitated amide was filtered off and dried at110° C., m.p. 287°-291° C.

B. Preparation of 3-Cyanothioxanthone

Thioxanthone-3-carboxamide (3.09 g) was dissolved in hotdimethylformamide (50 ml) and cooled to -30° C., whereupon the solidstarting material separated. Thionyl chloride (7.5 ml) was addeddropwise over 10 min. to the stirred mixture at -20° to -+° C., and themixture was then stirred in an ice bath for 2 hours, during which timethe temperature rose to 5° C. Some residual solid was left. The mixturewas poured into ice-water and the greenish-yellow product was filteredoff and dried at 110° C., m.p. 255°-256° C. (softens 251° C.).

C. Preparation of 3-(5-Tetrazolyl)thioxanthone

A mixture of 3-cyanothioxanthone (2.56 g), sodium azide (0.84 g) andammonium chloride (0.70 g) in dimethylformamide (20 ml) was heated on asteam bath for 5 hrs. The nitrile dissolved after 2 hrs., at the sametime a precipitate of the product forming. Much solid crystallised outon cooling. The reaction mixture was poured into excess dilutehydrochloric acid, and the yellow precipitate was filtered off andwashed with water. It was dissolved in dilute aqueous sodium hydroxide,filtered and reprecipitated with dilute hydrochloric acid. The productwas filtered off and dried at 110° C., and then recrystallised fromdimethylformamide and dried at 154° C./15 mm Hg, decomposes 290° C.

D. Preparation of 3-(5-Tetrazolyl)thioxanthone-10,10-dioxide

3-(5-Tetrazolyl)thioxanthone (0.40 g) was boiled with 30% hydrogenperoxide (0.80 ml) in acetic acid (30 ml) for 1 hr. The resultingcolourless solution was diluted with an equal volume of water, filteredwhile hot and cooled to yield the 10,10-dioxide, m.p. 257° C.(decomposition).

EXAMPLE 20 3-Carboxy-7-methylthioxanthone-10,10-dioxide A. Preparationof 2-(p-tolylthio)terephthalonitrile

To a solution of sodium methoxide (made from sodium (2.18 g) in methanol(50 ml) was added p-toluene thiol (11.8 g). The solution was evaporatedto dryness and the residual sodium salt dissolved in drydimethylsulphoxide (150 ml). Nitroterephthalonitrile (15.56 g) was addedand the resulting dark solution was heated on the steam bath for 30min., then poured into water. The precipitated product was filtered off,washed with water and dried at room temperature in vacuo, m.p. 155° C.

B. Preparation of 2-(p-tolylthio)terephthalic acid

The dinitrile (14.5 g) was dissolved in ethanol (100 ml) and sodiumhydroxide (9.5 g) in water (100 ml) was added. The mixture was boiledunder reflux for 30 min., the ethanol distilled off and the residualsolution filtered and boiled for a further 71/2 hours. It was thenpoured on to excess hydrochloric acid and ice and the precipitated acidfiltered off, washed with water, and dried at 100° C., m.p. 326° C.(decomposes).

C. Preparation of 7-methylthioxanthone-3-carboxylic acid

2-(p-Tolylthio)terephthalic acid (13.5 g) was stirred and heated withpolyphosphoric acid (330 g) at 100° C. for 3 hours. The mixture wasdecomposed with water and the ochre-coloured acid filtered off andrecrystallised from acetic acid, m.p. 321°-323° C.

D. Preparation of 3-carboxy-7-methylthioxanthone-10,10-dioxide

7-Methylthioxanthone-3-carboxylic acid (4.0 g) was dissolved in aceticacid (400 ml) and 30% hydrogen peroxide (15 ml) was added. The mixturewas boiled under reflux for 2 hours and cooled. The product, whichcrystallised out, was filtered off and dried at 110° C., m.p. 357° C(decomposes).

EXAMPLE 21 3-Carbamoyl-7-Methylthioxanthone-10,10-dioxide

3-Carboxy-7-methylthioxanthone-10,10-dioxide (0.99 g) was boiled withthionyl chloride (10 ml) containing 1 drop dimethyl formamide for 2hours. The solution was evaporated to dryness and the solid acidchloride residue added to 15% ammonia solution (30 ml) with stirring.After 1 hour the amide was filtered off, washed with water, and dried at100° C., m.p. 305° C. (decomposes).

EXAMPLE 22 7-Methyl-3-(5-tetrazolyl)thioxanthone-10,10-dioxide A.Preparation of 3-Cyano-7-methylthioxanthone-10,10-dioxide

The amide (0.79 g) of Example 21 was added to a mixture of dimethylformamide (100 ml) and thionyl chloride (2.0 ml) at -10° C., and stirredat -10° C. for 2 hrs. The mixture was poured on to ice-water and theprecipitated product filtered off and washed with water, recrystallisedfrom dimethylformamide, and dried at 155° C./15 mm. Hg, m.p. 290° C.(decomposes).

B. Preparation of 7-methyl-3-(5-tetrazolyl)thioxanthone-10,10-dioxide

3-Cyano-7-methylthioxanthone-10,10dioxide (0.36 g), sodium azide (0.091g), ammonium chloride (0.081 g) and dimethyl formamide (5.0 ml) wereheated together on the steam bath for 7 hrs., poured on to ice andhydrochloric acid, and the precipitated tetrazole filtered off, washedwith water and recrystallised from acetic acid, m.p. 267° C.(decomposes).

EXAMPLE 23 3-Carboxythioxanthone-10,10-dioxide sodium salt

3-Carboxythioxanthone-10,10dioxide (2.88 g: 10 mmole) was dissolved in Nsodium hydroxide (10 ml) to give a dark-coloured solution, which wasthen evaporated to dryness under reduced pressure.

The solid residue was recrystallised from aqueous ethanol and theproduct dried at 100° C. A second crop was obtained from therecrystallisation liquors on standing. This was filtered off, and driedat 100° C. to yield the product, 3-carboxythioxanthone-10,10-dioxidesodium salt (hydrated). Further drying at 156° C./20m.m. Hg gave theanhydrous compound having the infra red spectrum shown in FIG. 2 whendispersed in a potassium bromide disc (Unicam SP 200 (Unicam InstrumentsLtd., Cambridge)).

EXAMPLE 24 3-(5-Tetrazolyl)thioxanthone-10,10-dioxide A.2-Phenylthio-4-(5-tetrazolyl)benzonitrile

Phenylthioterephthalonitrile (2.36g), sodium azide (0.65g) and ammoniumchloride (0.54g) were heated in dimethylformamide (25ml) on the steambath for 16 hrs. An insoluble deposit of sodium chloride formed. Thereaction mixture was poured into hydrochloric acid (50 ml, 0.6 normal).When the oily precipitate had crystallised it was filtered off,recrystallised from acetic acid, and dried in vacuo over potassiumhydroxide pellets, m.p. 187° C.

B. 2-Phenylthio-4-(5-tetrazolyl)benzoic acid

2-Phenylthio-4-(5-tetrazolyl)benzonitrile (1.89g) was dissolved in 0.5normal sodium hydroxide solution (100 ml) and boiled for 9.5 hrs. Thesolution was poured on to ice and excess hydrochloric acid, and theprecipitated product filtered off and recrystallised from acetic acid,m.p. 239°-240° C.

C. 2-Phenylsulphonyl-4-(5-tetrazolyl)benzoic acid

2-Phenylthio-4-(5-tetrazolyl)benzoic acid (4.20g), acetic acid (100 ml)and 30% hydrogen peroxide (20 ml) were boiled under reflux for 2 hr. Thesolution was cooled and evaporated and the residue recrystallised fromacetonitrile, with which the product formed a complex stable at 80°C./20 mm. Hg. The product was obtained pure by drying at 156° C./20 mm.Hg, the 2-phenylsulphonyl-4-(5-tetrazolyl)benzoic acid having m.p. 250°C. with decomposition.

D. 3-(5-Tetrazolyl)thioxanthone-10,10-dioxide hrs.

2-Phenylsulphonyl-4-(5-tetrazolyl)benzoic acid (200 mg) was heated withconcentrated sulphuric acid (10 ml) for 5 hrs. at 120° C. After coolingand dilution with water, a solid product separated and was filtered off,washed with water, and recrystallised from acetic acid to give3-(5-tetrazolyl)thioxanthone-10,10-dioxide, identified by its infraredspectrum.

EXAMPLE 25 3-Carboxythioxanthone-10,10-dioxide ethanolamine salt

To 3-carboxythioxanthone-10,10-dioxide (2.88g) was added a solution ofethanolamine (0.61g) in water (10 ml). The solution was filtered andevaporated to dryness, leaving a residue of3-carboxythioxanthone-10,10-dioxide ethanolamine salt, m.p. 195° C. withdecomposition.

Found: C, 54.98%; H, 4.33%; N, 3.93%. C₁₆ H₁₅ NO₆ S requires C, 55.01%;H, 4.33%; N, 4.01%.

EXAMPLE 26 7-Methoxy-3-(5-tetrazolyl)thioxanthone-10,10-dioxide A.7-Methoxy-3-(5-tetrazolyl)thioxanthone

7-methoxythioxanthone-3-carboxylic acid (6.0g) was boiled with thionylchloride (40 ml) and dimethylformamide (1 drop) for 1 hr., filtered andevaporated. The residual acid chloride was recrystallised from tolueneand treated with 0.880 ammonia (40 ml) boiling gently for 40 min. Theamide (m.p. 299°-301° C.) was filtered off, dried, dissolved in hotdimethylformamide (50 ml) and cooled to -30° C. Thionyl chloride (5.0ml) was added with stirring, and the temperature maintained at -30° C.for 30 min. The solution was poured onto ice and the nitrile (m.p.251°-255° C.) filtered off and dried.

The nitrile, sodium azide (0.38g), ammonium chloride (0.31g) anddimethylformamide (20 ml) were heated together at 130° C. for 3 hrs.,cooled and diluted with sodium hydroxide solution. The solution wasfiltered and acidified with hydrochloric acid. The product was filteredoff and recrystallised from acetic acid, to yield7-methoxy-3-(5-tetrazolyl)thioxanthone m.p. > 350° C.

Found: C, 57.70%; H, 3.39%; N, 17.97%. C₁₅ H₁₀ N₄ O₂ S requires C,58.06%; H, 3.25%; n, 18.06%.

B. 7-Methoxy-3-(5-tetrazolyl)thioxanthone-10,10-dioxide

7-Methoxy-3-(5-tetrazolyl)thioxanthone (0.50g), acetic acid (25 ml) and30% hydrogen peroxide (1.0 ml) were boiled together under reflux for 45min. On cooling, 7-methoxy-3-(5-tetrazolyl) thioxanthone-10,10-dioxideseparated, and was filtered off and recrystallised from acetic acid,m.p. 253° C. with decomposition.

Found: C, 52.51%; H, 3.03%; N, 16.09%. C₁₅ H₁₀ N₄ O₄ S requires C,52.64%; H, 2.95%; N, 16.37%.

EXAMPLE 27 3-Carboxy-7-nitrothioxanthone-10,10-dioxide A.7-Nitrothioxanthone-3-carboxylic acid

Sodium 4-nitrothiophenoxide (from 1.55g of 4-nitrothiophenol) was heatedwith 2.5-dicyanonitrobenzene (1.73g) in dimethylsulphoxide (30 ml) at100° C. for 1hr. After standing overnight the solution was diluted withwater and dilute sodium carbonate and the precipitate of2,5-dicyano-4'-nitrodiphenylsulphide (2.65g) collected by filtration.This compound had m.p. 181° C. when recrystallised. To hydrolyse thedinitrile, it was refluxed with a mixture of 60% w/w sulphuric acid (70ml) and glacial acetic acid (45 ml) for 3.5 hr. and the resultingp-nitrothiophenoxyterephthalic acid filtered off. This was cyclised byheating with an excess of phosphorus oxychloride for 24 hrs., removingthe solvent under reduced pressure, and again heating for 21 hr. at 135°C. with an excess of polyphosphoric acid. On addition to warm water2-nitrothioxanthone-6-carboxylic acid was precipitated; from a mixtureof dimethylformamide, dimethylsulphoxide and ethanol, the acid formedcrystals which sublimed but did not melt up to 410° C.

B. 3-Carboxy-7-nitrothioxanthone-10,10-dioxide

7-Nitrothioxanthone-3-carboxylic acid (0.65g), acetic acid (125 ml) and30% hydrogen peroxide (3.0 ml) were boiled together under reflux for 18hr. The solution was filtered off and 3-carboxy-7-nitrothioxanthone-10,10-dioxide crystallised out slowly andwas filtered off and dried at 156° C. in vacuo, m.p. > 360° C.

Found: C, 50.49%; H, 2.30%; N, 4.05%. C₁₄ H₇ NO₇ S requires C, 50.46%;H, 2.12%; N, 4.20%.

EXAMPLE 28 2,5-Dicarboxythioxanthone-10,10-dioxide A.Thioxanthone-2,5-dicarboxylic acid

Sodium 4-cyanothiophenoxide (from 2.7g of 4cyanothiophenol) was heatedwith 2.6-dicyanonitrobenzene (3.5g) in dimethylsulphoxide (20 ml) at110° C. overnight. On dilution with water,2,4',6-tricyanodiphenylsulphide, m.p. 172°-173° C., was obtained. Thiswas hydrolysed by refluxing for 5 hrs. in 60% sulphuric acid (40 ml) andglacial acetic acid (25 ml); a solid precipitate ofdiphenylsulphide-2,4',6-tricarboxylic acid being formed. This wascyclised in concentrated sulphuric acid at 90°-100° C.; after 4 hrs.heating the solution was poured onto ice. The resultingthioxanthone-2,5-dicarboxylic acid, on crystallisation fromdimethylformamide-ethanol, formed crystals, m.p. ca. 400° C., whichcontained one quarter of a molecule of dimethyl formamide of solvation.

B. 2,5-Dicarboxythioxanthone-10,10-dioxide

Thioxanthone-2,5-dicarboxylic acid (0.52g), acetic acid (25 ml) and 30%hydrogen peroxide (1.5 ml) were boiled together under reflux for 2.5 hr.Further acetic acid (ca. 100 ml) was added to dissolve all of theproduct, the solution was filtered while boiling, and on cooling2,5-dicarboxythioxanthone-10,10-dioxide crystallised out and wasfiltered off and dried, m.p. 350°-351° C.

Found: C, 53.94%; H, 2.46%. C₁₅ H₈ O₇ S requires C, 54.22%; H, 2.43%.

EXAMPLE 29 1-Carboxythioxanthone-10,10-dioxide A.Thioxanthone-1-carboxylic acid

Sodium thiophenoxide (from 3.3g of thiophenol) was heated at 100° C. indimethylsulphoxide (30 ml) with 2,3-dicyanonitrobenzene (5.2g) for 4.5hrs. On dilution with water, 3-thiophenoxyphthalodinitrile, m.p.116°-117° C., was obtained. This was refluxed with 60% sulphuric acid(105 ml) and acetic acid (66 ml) for 5.5 hrs. to give the correspondingphthalic acid, which was then cyclized by heating with an excess ofpolyphosphoric acid for 72 hrs. at 135°-145° C. Addition to warm watergave a precipitate of thioxanthone-1-carboxylic acid which yieldedcrystals, m.p. 264°-265° C. from a mixture of dimethyl formamide andaqueous ethanol.

B. 1-Carboxythioxanthone-10,10-dioxide

Thioxanthone-1-carboxylic acid (0.60g), acetic acid (15 ml) and 30%hydrogen peroxide solution (0.60 ml) were boiled under reflux togetherfor 8 hrs., during which time a further two (0.60 ml) portions ofperoxide were added at intervals. The boiling solution was filtered, andon cooling 1-carboxythioxanthone-10,10-dioxide crystallised out and wasfiltered off and dried, m.p. 269°-271° C.

Found: C, 58.08%; H, 2.84%. C₁₄ H₈ O₅ S requires C, 58.33%; H, 2.80%.

EXAMPLE A Compression Coated Tablet

    ______________________________________                                        Core   3-(5-Tetrazolyl)thioxanthone-10,10-dioxide                                                              100mg                                                sodium salt                                                                  Starch B.P.                25mg                                               Magnesium Stearate B.P.    2mg                                         Coating                                                                              Lactose B.P.              320mg                                               Starch B.P.                50mg                                               Gelatin B.P.               6mg                                                Magnesium Stearate B.P.    4mg                                         ______________________________________                                    

Sodium Tetrazolyl salt and starch were granulated with water and dried.Magnesium stearate was added to the dried granule. Lactose and starchwere granulated with a 10% w/v aqueous solution of gelatin and dried.Magnesium stearate was added to the dried granule.

The granulated core was compressed with the granulated coating in aconventional compression moulding machine.

EXAMPLE B - Capsule

    ______________________________________                                        3-(5-Tetrazolyl)thioxanthone-10,                                                                       1.5 g                                                10-dioxide sodium salt.                                                       Sorbitan Monolaurate     0.6 g                                                Polysorbate 20           0.6 g                                                Cetostearyl Alcohol      1.2 g                                                Glycerin                 6.0 g                                                Methyl Hydroxybenzoate   0.2 g                                                Purified Water B.P.   to 100.0 ml                                             ______________________________________                                    

Sodium tetrazolyl salt, lactose and talc were brought into intimateadmixture with one another and 440mg of the resultant mixture wasintroduced into a size O hard gelatin capsule.

    ______________________________________                                        3-(5-Tetrazolyl)thioxanthone-10,10-dioxide                                                               200mg                                               sodium salt                                                                  Lactose B.P.               200mg                                              Talc B.P.                   40mg                                              ______________________________________                                    

EXAMPLE C Lotion for Topical Use

    ______________________________________                                        3-(5-Tetrazolyl)thioxanthone-10,                                                                       1.5 g                                                10-dioxide sodium salt.                                                       Sorbitan Monolaurate     0.6 g                                                Polysorbate 20           0.6 g                                                Cetostearyl Alcohol      1.2 g                                                Glycerin                 6.0 g                                                Methyl Hydroxybenzoate   0.2 g                                                Purified Water B.P.   to 100.0 ml                                             ______________________________________                                    

The Methyl Hydroxybenzoate and Glycerin were dissolved in 70 ml. of theWater at 75° C. The Sorbitan Monolaurate, Polysorbate 20 and CetostearylAlcohol were melted together at 75° C. and added to the aqueoussolution. The resulting emulsion was homogenised, allowed to cool withcontinuous stirring and the Sodium Tetrazolyl salt added as a solutionin the remaining Water. The whole was stirred until homogeneous.

EXAMPLE D Inhalation Aerosol

    ______________________________________                                        3-Carboxythioxanthone-10,10-dioxide                                            (0.5 - 7.0 μm powder)                                                                              200    mg                                            Sorbitan Trioleate       100    mg                                            Saccharin Sodium                                                               (0.5 - 7.0 μm powder)                                                                              5      mg                                            Menthol                  2      mg                                            Trichlorofluoromethane   4.5    g                                             Dichlorodifluoromethane  10.0o  ml                                            ______________________________________                                    

The Sorbitan Trioleate and Menthol were dissolved in theTrichlorofluoromethane. The Saccharin Sodium and Carboxylic Acid weredispersed in the mixture which was then transferred to a suitableaerosol canister and the Dichlorodifluoromethane injected through thevalve system. This composition provides 10 mg. of Acid in each 100 ml.dose.

EXAMPLE E Lozenge

    ______________________________________                                        3-(5-Tetrazolyl)thioxanthone-10,10-                                                                   50       mg                                           dioxide sodium salt.                                                          Mannitol                400      mg                                           Dextrose Monohydrate    400      mg                                           Magnesium Stearate      20       mg                                           Granulated with solution of Polyvinylipyrrolidone 5% w/v in                   25% w/v aqueous ethanol.                                                      ______________________________________                                    

The Sodium Tetrazolyl salt was mixed with the Dextrose Monohydrate andMannitol; granulated with the ethanolic Polyvinylpyrrolidone solutionand then dried. The Magnesium Stearate was sifted on and the resultingmixture compressed to produce lozenges of the desired shape.

EXAMPLE F Capsule

    ______________________________________                                        3-(5-Tetrazolyl)thioxanthone-10,10-                                                                   100      mg                                           dioxide                                                                       Lactose                 100      mg                                           Maize Starch            100      mg                                           Magnesium Stearate      10       mg                                           ______________________________________                                    

The ingredients were mixed together until homogeneous and 310 mg of theresulting mixture filled into each hard gelatin capsule.

EXAMPLE G Tablet

    ______________________________________                                        3-Carboxythioxanthone-10,10-dioxide                                                                   500      mg                                           Maize Starch            100      mg                                           Microcrystalline Cellulose                                                                            75       mg                                           Magnesium Stearate      10       mg                                           Granulated with Polyvinylpyrrolidone 10% w/v in 50% w/v                       aqueous ethanol.                                                              ______________________________________                                    

The Carboxylic Acid, Maize Starch and Microcrystalline Cellulose weremixed together, and granulated with the alcoholic Polyvinylpyrrolidone.The resulting granules were dried, and compressed to produce tablets,each tablet having a weight of approximately 690 mg.

EXAMPLE H Foaming Non-aqueous Aerosol for Topical Use

    ______________________________________                                        3-Carboxythioxanthone-10,10-dioxide                                                                   5.0      g                                            (fine powder)                                                                 Polyethylene Glycol 400 80.0     g                                            Propylene Glycol Monostearate,                                                self-emulsifying        5.0      g                                            Dichlorodifluoromethane (Propellant 12)                                                               4.0      g                                            Dichlorotetrafluoroethane                                                     (Propellant 114)        6.0      g                                            ______________________________________                                    

The Carboxylic acid was dispersed in a mixture of the Propylene GlycolMonostearate, self-emulsifying, and the Propylene Glycol. An aerosolcanister, was filled with the mixture, the valve sealed on andpressurisation effected by injecting the propellents through the valve.

EXAMPLE I Foaming Aqueous Aerosol for Topical Use

    ______________________________________                                        Part A   3-Carboxythioxanthone-10,10-                                                  dioxide sodium salt  2.2     g                                                Triethanolamine      3.2     g                                                Glycerin             4.7     g                                                Polyvinylpyrrolidone 0.3     g                                                Purified Water B.P.  81.0    g                                       Part B   Myristic Acid        1.3     g                                                Stearic Acid         5.3     g                                                Cetyl Alcohol        0.5     g                                                Lanolin              0.2     g                                                Isopropyl Myristate  1.3     g                                       Propellents                                                                            Dichlorodifluoremethane                                                                            4.0     g                                                Dichlorotetrafluoroethane                                                                          6.0     g                                       ______________________________________                                    

The ingredients of Part B were melted together at 70° C. A solution ofthe ingredients of Part A in the Purified Water at the same temperature,was added to the melted ingredients of Part B. The resulting emulsionwas homogenised and cooled to room temperature. The emulsion was filledinto an aerosol canister, the valve crimped on and pressurisationeffected by injecting the mixed propellents through the valve.

EXAMPLE J Spray on Film for Topical Use

    ______________________________________                                        3-(5-Tetrazolyl)thioxanthone-10,10-                                                                   5.0      g                                            dioxide (fine powder)                                                         Polyethylene Glycol 600 0.8      g                                            Menthol                 0.01     g                                            Acetone                 43.5     g                                            Ethyl Alcohol Absolute  45.69    g                                            Polyvinylpyrrolidone/Vinyl Acetate                                            Copolymer (40:60) (PVP/VA)                                                                            5.0      g                                            Dichlorodifluoromethane (Propellant 12)                                                               30.0     g                                            Dichlorotetrafluoroethane                                                     (Propellant 114)        70.0     g                                            ______________________________________                                    

The Polyethylene Glycol 600, Menthol and PVP/VA Copolymer were dissolvedin a mixture of the Acetone and Ethyl Alcohol. The Carboxylic Acid wasadded and dispersed. The mixture was transferred to a suitable aerosolcanister, the valve crimped on and pressurisation effected by injectingthe mixture of propellents through the valve.

EXAMPLE K Nasal Drops

    ______________________________________                                        3-Carboxythioxanthone-10,10-dioxide                                                                   5.0      g                                            sodium salt                                                                   Chlorbutol              0.5      g                                            Purified Water B.P.    to                                                                             100.0    ml                                           ______________________________________                                    

The ingredients were dissolved in 95 ml. Purified water at roomtemperature. The resulting mixture was made up to 100mls with PurifiedWater and clarified by filtration.

EXAMPLE L Eye Drops

    ______________________________________                                        3-Carboxythioxanthone-10,10-dioxide                                                                   5.0      g                                            sodium salt                                                                   Methyl Hydroxybenzoate  0.10     g                                            Propyl Hydroxybenzoate  0.04     g                                            Purified Water B.P.    to                                                                             100.00   ml                                           ______________________________________                                    

The Methyl and Propyl Hydroxybenzoates were dissolved in 70 ml. PurifiedWater at 75° C. and the resulting solution then allowed to cool. Thesodium carboxylate salt was added next and the solution made up to 100ml. with purified water. The solution was sterilised by filtrationthrough a membrane filter 0.22μm pore size and packed aseptically intosuitable sterile containers.

EXAMPLE M Powder Capsules for Inhalation

    ______________________________________                                        3-(5-Tetrazolyl)thioxanthone-10,10-                                           dioxide sodium salt (0.5-7.0 μm powder)                                                            4.0       mg                                          Lactose (30-90 μm powder)                                                                          46.0      mg                                          ______________________________________                                    

The powders were mixed until homogeneous and filled into suitably sizedhard gelatin capsules, 50 mg of mixture per capsule.

EXAMPLE N Injection Solution

    ______________________________________                                        3-Carboxythioxanthone-10,10-                                                                          50.0     mg                                           dioxide sodium salt                                                           Water for Injections B.P.    to                                                                       1.0      ml                                           ______________________________________                                    

The sodium carboxylate salt was dissolved in half of the Water and thenmade up to volume and sterilised by filtration. The resulting solutionwas distributed into ampoules under aseptic conditions.

EXAMPLE O Suppositories

    ______________________________________                                        3-Carboxythioxanthone-10,10-dioxide                                                                   200      mg                                           Suppository Base        1.8      g                                            ______________________________________                                    

The carboxylic acid in fine powder form was dispersed into a little ofthe molten Suppository Base at 50° C. The dispersion was incorporatedinto the bulk of the base at the same temperature, allowed to cool at42°-45° C. and poured into suitable 2g suppository moulds and allowed toset at 15°-20° C. Suppository Bases were Massa Esterinum C and Witten HSuppository Compound.

EXAMPLE P Dispersible Tablet

    ______________________________________                                                              Per tablet                                              ______________________________________                                        3-carboxythioxanthone-10,10-dioxide                                                                   200.00   mg                                           Maize Starch            40.00    mg                                           Primojel (Trade name: sodium starch                                           glycollate (125 μm powder)                                                                         50.00    mg                                           Dicalcium Phosphate Dihydrate                                                                         50.00    mg                                           Sodium Carboxymethyl Cellulose                                                                        2.00     mg                                           Dioctyl Sodium Sulphosuccinate                                                                        0.25     mg                                           Sodium Saccharin        5.00     mg                                           Microcrystalline Cellulose                                                                            50.00    mg                                           Magnesium Stearate      3.00                                                                          400.25   mg                                           ______________________________________                                    

The carboxylic acid, half of the Maize Starch, the Primojel andDicalcium Phosphate were mixed together and then granulated with asolution of Sodium Carboxymethyl Cellulose, Dioctyl SodiumSulphosuccinate and Sodium Saccharin in a suitable volume of 50% EthylAlcohol. The granules were dried, the remaining Maize Starch, theMicrocrystalline Cellulose and the Magnesium Stearate were blended inand the resulting mixture compressed into tablets each having a weightof 400.25 mg. ##STR3##

What we claim is:
 1. A method of preventing the symptoms of allergicconditions consisting of asthma, allergic rhinitis, conjunctivitis,urticaria or eczema of a mammal in need thereof comprisingadministration to the mammal of a prophylactically effective amount of atricyclic compound of formula Iwherein Z¹ is a substituent in the 1-,2-, 3-, or 4- position and is 5-tetrazolyl, 5-(1-alkyl)tetrazolyl, or5-(2-alkyl)tetrazolyl in which the alkyl has 1 to 6 carbon atoms and areeach optionally substituted by hydroxyl; Z² is hydrogen when (a) Z¹ isin the 1-, 2-, or 4-position and has the same meaning as above and (b)when Z¹ is in the 3-position and is 5-(1-alkyl)tetrazolyl or5-(2-alkyl)tetrazolyl in which the alkyl has 1 to 6 carbon atoms and areeach optionally substituted by a hydroxyl or carboxyl; or Z² is asubstituent in the 5-, 6-, 7-, or 8-position selected from the groupconsisting of Z¹ as defined above, carboxyl, alkylsulphonyl,alkylsulphinyl, thioalkyl, amino, nitro, cyano, halogen, alkyl or alkoxywherein the "alkyl" moiety of each of the alkyl, alkoxy, thioalkyl,alkylsulphinyl and alkylsulphonyl has 1 to 6 carbon atoms; and Z³ iscarbonyl; or a pharmaceutically acceptable salt thereof.
 2. A method asclaimed in claim 1 wherein the tricyclic compound is of formula II##STR4## wherein Z¹ is a substituent in the 3-position and is5-tetrazolyl and Z² is a substituent in the 5-, 6-, 7-, or 8-positionselected from carboxyl, 5-tetrazolyl, nitro, chloro, bromo, or alkylhaving 1 to 3 carbon atoms; or a pharmaceutically acceptable saltthereof.
 3. A method as claimed in claim 1 wherein the tricycliccompound is of formula V ##STR5## wherein Z³ is as defined in claim 1,Z¹ is selected from the group consisting of 5-tetrazolyl and a5-tetrazolyl salt and Z² is selected from the group consisting ofcarboxyl, a pharmaceutically acceptable carboxylate salt, alkylcarboxylate having 1 to 6 carbon atoms in the alkyl moiety thereof,carboxamide optionally N-substituted by alkyl having 1 to 6 carbonatoms, 5-tetrazolyl, and a 5-tetrazolyl salt.
 4. A method as claimed inclaim 1 wherein the tricyclic compound is selected from the groupconsisting of 7-methyl-3-(5-tetrzolyl) thioxanthone-10,10-dioxide; and apharmaceutically acceptable salt thereof.
 5. A method as claimed inclaim 4 wherein said salt is the sodium salt.
 6. A method as claimed inclaim 4 wherein said tricyclic compound or salt thereof is administeredby the oral route.
 7. A method as claimed in claim 6 wherein saidtricyclic compound or salt thereof is administered at a dose of 1 to 50mg. per kilogram body weight of said mammal.
 8. A method as claimed inclaim 7 wherein said allergic condition is allergic asthma.
 9. A methodas claimed in claim 7 wherein said allergic condition is hay fever. 10.A method as claimed in claim 1 wherein administration is effected by thepulmonary route.
 11. A method as claimed in claim 10 wherein thetricyclic compound is administered as a powder having a particle size inthe range of 0.5 to 7μ.
 12. A method as claimed in claim 11 wherein thetricyclic compound is administered at a dose of 5μ to 0.5 mg. perkilogram body weight of said mammal.
 13. A method as claimed in claim 1wherein administration is effected by the oral route.
 14. A method asclaimed in claim 13 wherein the tricyclic compound is administered at adose of 1 to 50 mg. per kilogram body weight of said mammal.
 15. Amethod as claimed in claim 1 wherein the tricyclic compound is offormula III ##STR6## wherein Z¹ is a substituent in the 1-, 2-, 3-, or4-position and is 5-tetrazolyl, 5-tetrazolyl salt, 5-(1-alkyl)tetrazolylor 5-(2-alkyl)tetrazolyl in which the alkyl has 1 to 6 carbon atoms, Z²is hydrogen (a) Z¹ is in the 1-, 2-, or 4-position and has the samemeaning as above and (b) when Z¹ is in the 3-position and is carboxyl,5-(1-alkyl)tetrazolyl, or 5-(2-alkyl)tetrazolyl in which the alkyl has 1to 6 carbon atoms and are each optionally substituted by hydroxyl, or Z²is a substituent in the 5-, 6-, 7-, or 8-position and has the samevalues as the group Z¹ as defined above or is alkylsulphonyl,alkylsulphinyl, thioalkyl, amino, nitro, cyano, halogen, alkanoyl, alkylor alkoxy wherein the "alkyl" moiety of each of the alkyl and alkoxy,have 1 to 6 carbon atoms and Z³ is carbonyl.
 16. A method of preventingthe symptoms of allergic conditions consisting of asthma, allergicrhinitis, conjunctivitis, urticaria or eczema of a mammal in needthereof comprising administration to the mammal of a prophylacticallyeffective amount of a tricyclic compound of formula XI wherein ##STR7##Z³ is carbonyl Z¹ is a substituent in the 1-, 2-, 3-, or 4-position andis 5-tetrazolyl, a 5-tetrazolyl salt, 5-(1-alkyl)tetrazolyl or5-(2-alkyl)tetrazolyl in which the alkyl groups have 1 to 6 carbon atomsand are each optionally substituted by hydroxy, carboxyl and Z² ishydrogen when (a) Z¹ is in the 1-, 2-, or 4-position and has the samemeaning as above and (b) when Z¹ is in the 3-position and is5-(1-alkyl)tetrazolyl, or 5-(2-alkyl)tetrazolyl in which the alkylgroups have 1 to 6 carbon atoms and are each optionally substituted byhydroxy, carboxyl or Z² is a substituent in the 5-, 6-, 7- or 8-positionselected from the values of the group Z¹ as defined above or isalkylsulphonyl, alkylsulphinyl, thioalkyl, amino, nitro, cyano, halogen,alkyl, or alkoxy wherein the "alkyl" moiety of each of the alkyl,alkoxy, thioalkyl, alkylsulphinyl and alkylsulphonyl has 1 to 6 carbonatoms, carboxyl, a carboxylate salt, alkyl carboxylate wherein the alkylmoiety has 1 to 6 carbon atoms, or a carboxamide group optionallyN-substituted by alkyl having 1 to 6 carbon atoms.
 17. A method ofpreventing the symptoms of allergic conditions consisting of asthma,allergic rhinitis, conjunctivitis, urticaria or eczema of a mammal inneed thereof comprising administration to the mammal of aprophylactically effective amount of a tricyclic compound of formula XII##STR8## wherein Z¹ is a substitutent in the 3-position and is a5-tetrazolyl or 5-tetrazolyl salt group; Z² is a substituent in the 5-,6-, 7- or 8-position selected from the values of the group Z¹ definedabove or is alkylsulphonyl, alkylsulphinyl, thioalkyl, amino, nitro,cyano, halogen, alkyl or alkoxy wherein the "alkyl" moiety of alkanoylalkoxy, thioalkyl, alkylsulphinyl and alkylsulphonyl has 1 to 6 carbonatoms or a carboxyl; and Z³ is carbonyl.
 18. A pharmaceuticalcomposition for use in preventing the symptoms of allergic conditionsconsisting of asthma, allergic rhinitis, conjunctivitis, urticaria oreczema comprising a prophylactically effective, non-toxic amount of atricyclic compound of formula I ##STR9## wherein Z¹ is a substituent inthe 1-, 2-, 3-, or 4-position and is 5-tetrazolyl,5-(1-alkyl)tetrazolyl, or 5-(2-alkyl) tetrazolyl in which the alkyl has1 to 6 carbon atoms and are each optionally substituted by a hydroxyl;Z² is hydrogen when (a) Z¹ is in the 3-position and is5-(1-alkyl)tetrazolyl or 5-(2-alkyl)tetrazolyl in which the alkyl has 1to 6 carbon atoms and are each optionally substituted by hydroxyl orcarboxyl; or Z² is a substituent in the 5-, 6-, 7- or 8-positionselected from the group consisting of Z¹ as defined above or iscarboxyl, alkylsulphonyl, alkylsulphinyl, thioalkyl, amino, nitro,cyano, halogen, alkyl or alkoxy wherein the "alkyl" moiety of each ofthe alkyl, alkoxy, thioalkyl, alkylsulphinyl and alkylsulphonyl has 1 to6 carbon atoms; and Z³ is carbonyl; or a pharmaceutically acceptablesalt thereof in association with a pharmaceutically acceptable carriertherefor.
 19. A pharmaceutical composition as claimed in claim 18wherein the pharmaceutically acceptable salt is selected from sodium,potassium, magnesium, calcium, or ammonium salts.
 20. A composition asclaimed in claim 18 wherein the composition is in the form of a discretedosage unit each containing an effective antiallergic, nontoxic amountof said tricyclic compound.
 21. A composition as claimed in claim 20wherein the composition is in the form of a tablet, capsule, lozenge orsachet.
 22. A composition as claimed in claim 20 wherein the compositionis in the form of a coated, moisture resistant tablet.
 23. A compositionas claimed in claim 20 wherein each discrete unit contains from 50 to500 mg. of said tricyclic compound.
 24. A pharmaceutical composition asclaimed to claim 18 wherein said tricyclic compound is in the form of apowder suitable for pulmonary administration.
 25. A composition asclaimed in claim 24 wherein the composition comprises a self-propellingaerosol composition in a sealed valved container in which said tricycliccompound is dispersed in a liquid propellant.
 26. A pharmaceuticalcomposition as claimed in claim 24 wherein said powdered tricycliccompound is incorporated in a capsule suitable for use in an inhalationdevice.
 27. A pharmaceutical composition for use in preventing thesymptoms of allergic conditions consisting of asthma, allergic rhinitis,conjunctivitis, urticaria or eczema comprising a prophylacticallyeffective non-toxic amount of a tricyclic compound of formula (II)##STR10## wherein Z¹ is a substituent in the 3-position and is5-tetrazolyl and Z² is hydrogen when (a) Z¹ is in the 1-, 2-, or4-position and has the same meaning as above and (b) when Z¹ is in the3-position and is carboxyl, 4-(1-alkyl) tetrazolyl, or5-(2-alkyl)tetrazolyl in which the alkyl has 1 to 6 carbon atoms and areeach optionally substituted by hydroxyl; and Z² is a substituent in the5-, 6-, 7- or 8-position selected from carboxyl, 5-tetrazoyly, nitro,chloro, bromo, or alkyl having 1 to 6 carbon atoms; or apharmaceutically acceptable salt thereof; in association with apharmaceutically acceptable carrier therefor.
 28. A pharmaceuticalcomposition for use in preventing the symptoms of allergic conditionsconsisting of asthma, allergic rhinitis, conjunctivitis, urticaria oreczema comprising a prophylactically effective non-toxic amount of atricyclic compound of formula III ##STR11## wherein Z¹ is a substituentin the 1-, 2-, 3-, or 4-position and is 5-tetrazolyl, a 5-tetrazolylsalt, a 5-(1-alkyl)tetrazolyl or a 5-(2-alkyl)tetrazolyl in which thealkyl has 1 to 6 carbon atoms and are each optionally substituted bycarboxyl; Z² is hydrogen when (a) Z¹ is in the 1-, 2-, or 4-position andhas the same meaning as above and (b) when Z¹ is in the 3-position andis 5-(1-alkyl)tetrazolyl or 5-(2-alkyl)tetrazolyl in which the alkyl has1 to 6 carbon atoms and are each optionally substituted by hydroxyl, orZ² is a substituent in the 5-, 6-, 6- or 8-position and has the samevalues as the group Z¹ as defined above or is a carboxyl, apharmaceutically acceptable carboxylate salt, a alkyl carboxylatewherein the alkyl moiety has 1 to 6, carbon atoms a carboxamideoptionally N-substituted by alkyl having 1 to 6 carbon atomsalkylsulphonyl, alkylsulphinyl, thioalkyl, amino, nitro, cyano, halogen,alkyl or alkoxy wherein the "alkyl" moiety of each of the alkyl, alkoxy,thioalkyl, alkylsulphinyl and alkylsulphonyl has 1 to 6 carbon atoms;and Z³ is carbonyl; in association with a pharmaceutically acceptablecarrier therefor.
 29. A pharmaceutical composition for use in preventingthe symptoms of allergic conditions consisting of asthma, allergicrhinitis, conjunctivitis, urticaria or eczema comprising aprophylactically non-toxic amount of a tricyclic compound of formula V##STR12## wherein Z³ is carbonyl, Z¹ is selected from 5-tetrazolyl and a5-tetrazolyl salt and Z² is selected from carboxyl, a pharmaceuticallyacceptable carboxylate salt, alkyl carboxylate having 1 to 6 carbonatoms in the alkyl moiety thereof, carboxamide optionally N-substitutedby alkyl having 1 to 6 carbon atoms, 5-tetrazolyl, and a 5-tetrazolylsalt in association with a pharmaceutically acceptable carrier therefor.30. A pharmaceutical composition for use in preventing the symptoms ofallergic conditions consisting of asthma, allergic rhinitis,conjunctivitis, urticaria or eczema comprising a prophylacticallyeffective non-toxic amount of 7-methyl-3-(5-tetrazolyl) thioxanthone-10,10-dioxide; or a pharmaceutically acceptable salt thereof; inassociation with a pharmaceutically acceptable carrier therefor.
 31. Apharmaceutical composition for use in preventing the symptoms ofallergic conditions consisting of asthma, allergic rhinitis, comprisingeffective non-toxic amount of a tricyclic comound of formula X1 wherein##STR13## Z³ is carbonyl; Z¹ is a substituent in the 1-, 2-, 4-, or4-position and is 5-tetrazolyl, a 5-tetrazolyl salt,5-(1-alkyl)tetrazolyl or 5-(2-alkyl)tetrazolyl in which the alkyl groupshave 1 to 6 carbon atoms and are each optionally substituted by ahydroxyl group, carboxyl; and Z² is hydrogen when (a) Z¹ is in the 1-,2-, or 4-position and has the same meaning as above and (b) when Z¹ isin the 3-position and is 5-(1-alkyl)tetrazolyl or 5-(2-alkyl)tetrazolylin which the alkyl has 1 to 6 carbon atoms and are each optionallysubstituted by hydroxyl; or Z² is a substituent in the 5-, 6-, 7- or8-position selected from the values of Z¹ as defined above or isalkylsulphonyl, alkylsulphinyl, thioalkyl, amino, nitro, cyano, halogen,alkyl, or alkoxy wherein the "alkyl" moiety of each of the alkyl,alkoxy, thioalkyl, alkylsulphinyl and alkylsulphonyl groups has 1 to 6carbon atoms, carboxyl, a carboxylate salt group, an alkyl carboxylategroup wherein the alkyl moiety has 1 to 6 carbon atoms, or carboxamideoptionally N-substituted by alkyl having 1 to 6 carbon atoms.
 32. Apharmaceutical composition for use in preventing the symptoms ofallergic conditions consisting of asthma, allergic rhinitis, uticaria,conjunctivitis or eczema comprising a prophylactically effectivenon-toxic amount of a tricyclic compound of formula XII ##STR14##wherein Z¹ is a substituent in the 3-position and is a 5-tetrazolyl or5-tetrazolyl salt; Z² is a substituent in the 5-, 6-, 7- or 8-positionselected from the group consisting of Z¹ defined above, alkylsulphonyl,alkylsulphinyl, thioalkyl, amino, nitro, cyano, halogen, alkyl or alkoxywherein the "alkyl" moiety of alkoxy, alkyl, thioalkyl, alkylsulphinyland alkylsulphonyl has 1 to 6 carbon atoms, and carboxyl, and Z³ iscarbonyl.